Substituted indazoles as glucokinase activators

ABSTRACT

Compounds are provided for use with hexokinases that comprise: 
                         
wherein the variables are as defined herein. Also provided are pharmaceutical compositions, kits and articles of manufacture comprising such compounds; methods and intermediates useful for making the compounds; and methods of using said compounds.

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.60/803,580, filed May 31, 2006, which is incorporated herein byreference.

FIELD OF THE INVENTION

The present invention relates to compounds that may be used to activatehexokinases, as well as compositions of matter, kits and articles ofmanufacture comprising these compounds. The invention also relates tomethods for activating hexokinases and treatment methods using compoundsaccording to the present invention. In addition, the invention relatesto methods of making the compounds of the present invention, as well asintermediates useful in such methods. In particular, the presentinvention relates to glucokinase activators, compositions of matter,kits and articles of manufacture comprising these compounds, methods foractivating glucokinase, and methods and intermediates useful for makingthe activators.

BACKGROUND OF THE INVENTION

Glucokinase (GK, Hexokinase IV) is one of four hexokinases that arefound in mammals (Colowick, S. P., in The Enzymes, Vol. 9 (P. Boyer,ed.) Academic Press, New York, N.Y., pages 1-48, 1973). The hexokinasescatalyze the first step in the metabolism of glucose, i.e., theconversion of glucose to glucose-6-phosphate. Glucokinase is foundprincipally in pancreatic β-cells and liver parenchymal cells, two celltypes that are known to play critical roles in whole-body glucosehomeostasis. Specifically, GK is a rate-controlling enzyme for glucosemetabolism in these two cell types (Chipkin, S. R., Kelly, K. L., andRuderman, N. B. in Joslin's Diabetes (C. R. Khan and G. C. Wier, eds.),Lea and Febiger, Philadelphia, Pa., pages 97-115, 1994).

The concentration of glucose at which GK demonstrates half-maximalactivity is approximately 8 mM. The other three hexokinases aresaturated with glucose at much lower concentrations (<1 mM). Therefore,the flux of glucose through the GK pathway rises as the concentration ofglucose in the blood increases from fasting levels (5 mM) topostprandial levels following a carbohydrate-containing meal (about10-15 mM) (Printz, R. G., Magnuson, M. A., and Granner, D. K. in Ann.Rev. Nutrition Vol. 13 (R. E. Olson, D. M. Bier, and D. B. McCormick,eds.), Annual Review, Inc., Palo Alto, Calif., pages 463-496, 1993).These findings suggest that GK functions as a glucose sensor in β-cellsand hepatocytes (Meglasson, M. D. and Matschinsky, F. M. Amer. J.Physiol. 246, E1-E13, 1984).

More recently, studies in transgenic animals confirmed that GK doesindeed play a critical role in whole-body glucose homeostasis. Animalsthat do not express GK die within days of birth with severe diabetes,while animals overexpressing GK have improved glucose tolerance (Grupe,A., Hultgren, B., Ryan, A. et al., Cell 83, 69-78, 1995; Ferrie, T.,Riu, E., Bosch, F. et al., FASEB J., 10, 1213-1218, 1996). An increasein glucose exposure is coupled through GK in β-cells to increasedinsulin secretion and in hepatocytes to increased glycogen depositionand perhaps decreased glucose production.

The finding that type II maturity-onset diabetes of the young (MODY-2)is caused by loss of function mutations in the GK gene suggests that GKalso functions as a glucose sensor in humans (Liang, Y., Kesavan, P.,Wang, L. et al., Biochem. J. 309, 167-173, 1995). Additional evidencesupporting an important role for GK in the regulation of glucosemetabolism in humans was provided by the identification of patients thatexpress a mutant form of GK with increased enzymatic activity. Thesepatients exhibit a fasting hypoglycemia associated with aninappropriately elevated level of plasma insulin (Glaser, B., Kesavan,P., Heyman, M. et al., New England J. Med. 338, 226-230, 1998).Accordingly, compounds that activate GK and, thereby, increase thesensitivity of the GK sensor system are expected to be useful in thetreatment of the hyperglycemia characteristic of all type II diabetes.Glucokinase activators should increase the flux of glucose metabolism inβ-cells and hepatocytes, which will be coupled to increased insulinsecretion.

There is a continued need to find new therapeutic agents to treat humandiseases. The hexokinases, specifically but not limited to glucokinase,are especially attractive targets for the discovery of new therapeuticsdue to their important role in diabetes, hyperglycemia and otherdiseases.

SUMMARY OF THE INVENTION

The present invention relates to compounds that activate glucokinase.The present invention also provides compositions, articles ofmanufacture and kits comprising these compounds. In addition, theinvention relates to methods of making the compounds of the presentinvention, as well as intermediates useful in such methods.

In one embodiment, a pharmaceutical composition is provided thatcomprises a glucokinase activator according to the present invention asan active ingredient. Pharmaceutical compositions according to theinvention may optionally comprise 0.001%-100% of one or more activatorsof this invention. These pharmaceutical compositions may be administeredor coadministered by a wide variety of routes, including for example,orally, parenterally, intraperitoneally, intravenously, intraarterially,transdermally, sublingually, intramuscularly, rectally, transbuccally,intranasally, liposomally, via inhalation, vaginally, intraoccularly,via local delivery (for example by catheter or stent), subcutaneously,intraadiposally, intraarticularly, or intrathecally. The compositionsmay also be administered or coadministered in slow release dosage forms.

The invention is also directed to kits and other articles of manufacturefor treating disease states associated with glucokinase.

In one embodiment, a kit is provided that comprises a compositioncomprising at least one glucokinase activator of the present inventionin combination with instructions. The instructions may indicate thedisease state for which the composition is to be administered, storageinformation, dosing information and/or instructions regarding how toadminister the composition. The kit may also comprise packagingmaterials. The packaging material may comprise a container for housingthe composition. The kit may also optionally comprise additionalcomponents, such as syringes for administration of the composition. Thekit may comprise the composition in single or multiple dose forms.

In another embodiment, an article of manufacture is provided thatcomprises a composition comprising at least one glucokinase activator ofthe present invention in combination with packaging materials. Thepackaging material may comprise a container for housing the composition.The container may optionally comprise a label indicating the diseasestate for which the composition is to be administered, storageinformation, dosing information and/or instructions regarding how toadminister the composition. The kit may also optionally compriseadditional components, such as syringes for administration of thecomposition. The kit may comprise the composition in single or multipledose forms.

Also provided are methods for preparing compounds, compositions and kitsaccording to the present invention. For example, several syntheticschemes are provided herein for synthesizing compounds according to thepresent invention.

Also provided are methods for using compounds, compositions, kits andarticles of manufacture according to the present invention.

In one embodiment, the compounds, compositions, kits and articles ofmanufacture are used to modulate glucokinase. In particular, thecompounds, compositions, kits and articles of manufacture can be used toactivate glucokinase.

In another embodiment, the compounds, compositions, kits and articles ofmanufacture are used to treat a disease state for which increasingglucokinase activity ameliorates the pathology and/or symptomology ofthe disease state.

In another embodiment, a compound is administered to a subject whereinglucokinase activity within the subject is altered and, in oneembodiment, increased.

In another embodiment, a prodrug of a compound is administered to asubject that is converted to the compound in vivo where it activatesglucokinase.

In another embodiment, a method of activating glucokinase is providedthat comprises contacting glucokinase with a compound according to thepresent invention.

In another embodiment, a method of activating glucokinase is providedthat comprises causing a compound according to the present invention tobe present in a subject in order to activate glucokinase in vivo.

In another embodiment, a method of activating glucokinase is providedthat comprises administering a first compound to a subject that isconverted in vivo to a second compound wherein the second compoundactivates glucokinase in vivo. It is noted that the compounds of thepresent invention may be the first or second compounds.

In another embodiment, a therapeutic method is provided that comprisesadministering a compound according to the present invention.

In another embodiment, a method of treating a condition in a patientthat is known to be mediated by glucokinase, or which is known to betreated by glucokinase activators, is provided comprising administeringto the patient a therapeutically effective amount of a compoundaccording to the present invention.

In another embodiment, a method is provided for treating a disease statefor which increasing glucokinase activity ameliorates the pathologyand/or symptomology of the disease state, the method comprising: causinga compound according to the present invention to be present in a subjectin a therapeutically effective amount for the disease state.

In another embodiment, a method is provided for treating a disease statefor which increasing glucokinase activity ameliorates the pathologyand/or symptomology of the disease state, the method comprising:administering a first compound to a subject that is converted in vivo toa second compound such that the second compound is present in thesubject in a therapeutically effective amount for the disease state. Itis noted that the compounds of the present invention may be the first orsecond compounds.

In another embodiment, a method is provided for treating a disease statefor which increasing glucokinase activity ameliorates the pathologyand/or symptomology of the disease state, the method comprising:administering a compound according to the present invention to a subjectsuch that the compound is present in the subject in a therapeuticallyeffective amount for the disease state.

In another embodiment, a method is provided for using a compoundaccording to the present invention in order to manufacture a medicamentfor use in the treatment of a disease state that is known to be mediatedby glucokinase, or that is known to be treated by glucokinaseactivators.

It is noted in regard to all of the above embodiments that the presentinvention is intended to encompass all pharmaceutically acceptableionized forms (e.g., salts) and solvates (e.g., hydrates) of thecompounds, regardless of whether such ionized forms and solvates arespecified since it is well known in the art to administer pharmaceuticalagents in an ionized or solvated form. It is also noted that unless aparticular stereochemistry is specified, recitation of a compound isintended to encompass all possible stereoisomers (e.g., enantiomers ordiastereomers depending on the number of chiral centers), independent ofwhether the compound is present as an individual isomer or a mixture ofisomers. Further, unless otherwise specified, recitation of a compoundis intended to encompass all possible resonance forms and tautomers.With regard to the claims, the language “compound comprising theformula,” “compound having the formula” and “compound of the formula” isintended to encompass the compound and all pharmaceutically acceptableionized forms and solvates, all possible stereoisomers, and all possibleresonance forms and tautomers unless otherwise specifically specified inthe particular claim.

It is further noted that prodrugs may also be administered which arealtered in vivo and become a compound according to the presentinvention. The various methods of using the compounds of the presentinvention are intended, regardless of whether prodrug delivery isspecified, to encompass the administration of a prodrug that isconverted in vivo to a compound according to the present invention. Itis also noted that certain compounds of the present invention may bealtered in vivo prior to activating glucokinase and thus may themselvesbe prodrugs for another compound. Such prodrugs of another compound mayor may not themselves independently have glucokinase activity.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates SEQ ID NO.: 1 referred to in this application.

DEFINITIONS

Unless otherwise stated, the following terms used in the specificationand claims shall have the following meanings for the purposes of thisApplication.

It is noted that, as used in the specification and the appended claims,the singular forms “a,” “an” and “the” include plural referents unlessthe context clearly dictates otherwise. Further, definitions of standardchemistry terms may be found in reference works, including Carey andSundberg “ADVANCED ORGANIC CHEMISTRY 4^(TH) ED.” Vols. A (2000) and B(2001), Plenum Press, New York. Also, unless otherwise indicated,conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry,biochemistry, recombinant DNA techniques and pharmacology, within theskill of the art are employed.

“Alicyclic” means a moiety comprising a non-aromatic ring structure.Alicyclic moieties may be saturated or partially unsaturated with one,two or more double or triple bonds. Alicyclic moieties may alsooptionally comprise heteroatoms such as nitrogen, oxygen and sulfur. Thenitrogen atoms can be optionally quaternerized or oxidized and thesulfur atoms can be optionally oxidized. Examples of alicyclic moietiesinclude, but are not limited to moieties with C₃₋₈ rings such ascyclopropyl, cyclohexane, cyclopentane, cyclopentene, cyclopentadiene,cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptene,cycloheptadiene, cyclooctane, cyclooctene, and cyclooctadiene.

“Aliphatic” means a moiety characterized by a straight or branched chainarrangement of constituent carbon atoms and may be saturated orpartially unsaturated with one, two or more double or triple bonds.

“Alkenyl” means a straight or branched, carbon chain that contains atleast one carbon-carbon double bond (—CR═CR′— or —CR═CR′R″, wherein R,R′ and R″ are each independently hydrogen or further substituents).Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl,hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and thelike. In particular embodiments, “alkenyl,” either alone or representedalong with another radical, can be a (C₂₋₂₀)alkenyl, a (C₂₋₁₅)alkenyl, a(C₂₋₁₀)alkenyl, a (C₂₋₅)alkenyl or a (C₂₋₃)alkenyl. Alternatively,“alkenyl,” either alone or represented along with another radical, canbe a (C₂)alkenyl, a (C₃)alkenyl or a (C₄)alkenyl.

“Alkenylene” means a straight or branched, divalent carbon chain havingone or more carbon-carbon double bonds (—CR═CR′—, wherein R and R′ areeach independently hydrogen or further substituents). Examples ofalkenylene include ethene-1,2-diyl, propene-1,3-diyl,methylene-1,1-diyl, and the like. In particular embodiments,“alkenylene,” either alone or represented along with another radical,can be a (C₂₋₂₀) alkenylene, a (C₂₋₁₅) alkenylene, a (C₂₋₁₀) alkenylene,a (C₂₋₅) alkenylene or a (C₂₋₃) alkenylene. Alternatively, “alkenylene,”either alone or represented along with another radical, can be a (C₂)alkenylene, a (C₃) alkenylene or a (C₄) alkenylene.

“Alkoxy” means an oxygen moiety having a further alkyl substituent. Thealkoxy groups of the present invention can be optionally substituted.

“Alkyl” represented by itself means a straight or branched, saturated orunsaturated, aliphatic radical having a chain of carbon atoms,optionally with one or more of the carbon atoms being replaced withoxygen (See “oxaalkyl”), a carbonyl group (See “oxoalkyl), sulfur (See“thioalkyl”), and/or nitrogen (See “azaalkyl”). (C_(X))alkyl and(C_(X-Y))alkyl are typically used where X and Y indicate the number ofcarbon atoms in the chain. For example, (C₁₋₆)alkyl includes alkyls thathave a chain of between 1 and 6 carbons (e.g., methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl,1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl,ethynyl, 1-propynyl, 2-propynyl, and the like). Alkyl represented alongwith another radical (e.g., as in arylalkyl, heteroarylalkyl and thelike) means a straight or branched, saturated or unsaturated aliphaticdivalent radical having the number of atoms indicated or when no atomsare indicated means a bond (e.g., (C₆₋₁₀)aryl(C₁₋₃)alkyl includes,benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-thienylmethyl,2-pyridinylmethyl and the like). In particular embodiments, “alkyl,”either alone or represented along with another radical, can be a(C₁₋₂₀)alkyl, a (C₁₋₁₅)alkyl, a (C₁₋₁₀)alkyl, a (C₁₋₅)alkyl or a(C₁₋₃)alkyl. Alternatively, “alkyl,” either alone or represented alongwith another radical, can be a (C₁)alkyl, a (C₂)alkyl or a (C₃)alkyl.

“Alkylene”, unless indicated otherwise, means a straight or branched,saturated or unsaturated, aliphatic, divalent radical. (C_(X))alkyleneand (C_(X-Y))alkylene are typically used where X and Y indicate thenumber of carbon atoms in the chain. For example, (C₁₋₆)alkyleneincludes methylene (—CH₂—), ethylene (—CH₂CH₂—), trimethylene(—CH₂CH₂CH₂—), tetramethylene (—CH₂CH₂CH₂CH₂—)2-butenylene(—CH₂CH═CHCH₂—), 2-methyltetramethylene (—CH₂CH(CH₃)CH₂CH₂—),pentamethylene (—CH₂CH₂CH₂CH₂CH₂—) and the like. In particularembodiments, “alkylene,” either alone or represented along with anotherradical, can be a (C₁₋₂₀)alkylene, a (C₁₋₁₅)alkylene, a (C₁₋₁₀)alkylene,a (C₁₋₅)alkylene or a (C₁₋₃)alkylene. Alternatively, “alkylene,” eitheralone or represented along with another radical, can be a (C₁)alkylene,a (C₂)alkylene or a (C₃)alkylene.

“Alkylidene” means a straight or branched, saturated or unsaturated,aliphatic radical connected to the parent molecule by a double bond.(C_(X))alkylidene and (C_(X-Y))alkylidene are typically used where X andY indicate the number of carbon atoms in the chain. For example,(C₁₋₆)alkylidene includes methylene (═CH₂), ethylidene (═CHCH₃),isopropylidene (═C(CH₃)₂), propylidene (═CHCH₂CH₃), allylidene(═CH—CH═CH₂), and the like. In particular embodiments, “alkylidene,”either alone or represented along with another radical, can be a(C₁₋₂₀)alkylidene, a (C₁₋₁₅)alkylidene, a (C₁₋₁₀)alkylidene, a(C₁₋₅)alkylidene or a (C₁₋₃)alkylidene. Alternatively, “alkylidene,”either alone or represented along with another radical, can be a(C₁)alkylidene, a (C₂)alkylidene or a (C₃)alkylidene.

“Alkynyl” means a straight or branched, carbon chain that contains atleast one carbon-carbon triple bond (—C≡C— or —C—CR, wherein R ishydrogen or a further substituent). Examples of alkynyl include ethynyl,propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like. In particularembodiments, “alkynyl,” either alone or represented along with anotherradical, can be a (C₂₋₂₀)alkynyl, a (C₂₋₁₅)alkynyl, a (C₂₋₁₀)alkynyl, a(C₂₋₅)alkynyl or a (C₂₋₃)alkynyl. Alternatively, “alkynyl,” either aloneor represented along with another radical, can be a (C₂)alkynyl, a(C₃)alkynyl or a (C₄)alkynyl.

“Alkynylene” means a straight or branched, divalent carbon chain havingone or more carbon-carbon triple bonds (—CR≡CR′—, wherein R and R′ areeach independently hydrogen or further substituents). Examples ofalkynylene include ethyne-1,2-diyl, propyne-1,3-diyl, and the like. Inparticular embodiments, “alkynylene,” either alone or represented alongwith another radical, can be a (C₂₋₂₀) alkynylene, a (C₂₋₁₅) alkynylene,a (C₂₋₁₀) alkynylene, a (C₂₋₅) alkynylene or a (C₂₋₃) alkynylene.Alternatively, “alkynylene,” either alone or represented along withanother radical, can be a (C₂) alkynylene, a (C₃) alkynylene or a (C₄)alkynylene.

“Amino” means a nitrogen moiety having two further substituents where,for example, a hydrogen or carbon atom is attached to the nitrogen. Forexample, representative amino groups include —NH₂, —NHCH₃, —N(CH₃)₂,—NH((C₁₋₁₀)alkyl), —N((C₁₋₁₀)alkyl)₂, —NH(aryl), —NH(heteroaryl),—N(aryl)₂, —N(heteroaryl)₂, and the like. Optionally, the twosubstituents together with the nitrogen may also form a ring. Unlessindicated otherwise, the compounds of the invention containing aminomoieties may include protected derivatives thereof. Suitable protectinggroups for amino moieties include acetyl, tert-butoxycarbonyl,benzyloxycarbonyl, and the like.

“Aminoalkyl” means an alkyl, as defined above, except where one or moresubstituted or unsubstituted nitrogen atoms (—N—) are positioned betweencarbon atoms of the alkyl. For example, an (C₂₋₆) aminoalkyl refers to achain comprising between 2 and 6 carbons and one or more nitrogen atomspositioned between the carbon atoms.

“Animal” includes humans, non-human mammals (e.g., dogs, cats, rabbits,cattle, horses, sheep, goats, swine, deer, and the like) and non-mammals(e.g., birds, and the like).

“Aromatic” means a moiety wherein the constituent atoms make up anunsaturated ring system, all atoms in the ring system are sp² hybridizedand the total number of pi electrons is equal to 4n+2. An aromatic ringmay be such that the ring atoms are only carbon atoms or may includecarbon and non-carbon atoms (See “heteroaryl”).

“Aryl” means a monocyclic or polycyclic ring assembly wherein each ringis aromatic or when fused with one or more rings forms an aromatic ringassembly. If one or more ring atoms is not carbon (e.g., N, S), the arylis a heteroaryl. (Cx)aryl and (Cx-y)aryl are typically used where X andY indicate the number of carbon atoms in the ring. In particularembodiments, “aryl,” either alone or represented along with anotherradical, can be a (C₃₋₁₄)aryl, a (C₃₋₁₀)aryl, a (C₃₋₇)aryl, a(C₈₋₁₀)aryl or a (C₅₋₇)aryl. Alternatively, “aryl,” either alone orrepresented along with another radical, can be a (C₅)aryl, a (C₆)aryl, a(C₇)aryl, a (C₈)aryl, a (C₉)aryl or a (C₁₀)aryl.

“Azaalkyl” means an alkyl, as defined above, except where one or more ofthe carbon atoms forming the alkyl chain are replaced with substitutedor unsubstituted nitrogen atoms (—NR— or —NRR′, wherein R and R′ areeach independently hydrogen or further substituents). For example, a(C₁₋₁₀)azaalkyl refers to a chain comprising between 1 and 10 carbonsand one or more nitrogen atoms.

“Bicycloalkyl” means a saturated or partially unsaturated fused, spiroor bridged bicyclic ring assembly. In particular embodiments,“bicycloalkyl,” either alone or represented along with another radical,can be a (C₄₋₁₅)bicycloalkyl, a (C₄₋₁₀)bicycloalkyl, a(C₆₋₁₀)bicycloalkyl or a (C₈₋₁₀)bicycloalkyl. Alternatively,“bicycloalkyl,” either alone or represented along with another radical,can be a (C₈)bicycloalkyl, a (C₉)bicycloalkyl or a (C₁₀)bicycloalkyl.

“Bicycloaryl” means a fused, spiro or bridged bicyclic ring assemblywherein at least one of the rings comprising the assembly is aromatic.(C_(X))bicycloaryl and (C_(X-Y))bicycloaryl are typically used where Xand Y indicate the number of carbon atoms in the bicyclic ring assemblyand directly attached to the ring. In particular embodiments,“bicycloaryl,” either alone or represented along with another radical,can be a (a (C₄₋₁₅)bicycloaryl, a (C₄₋₁₀)bicycloaryl, a(C₆₋₁₀)bicycloaryl or a (C₈₋₁₀)bicycloaryl. Alternatively,“bicycloalkyl,” either alone or represented along with another radical,can be a (C₈)bicycloaryl, a (C₉)bicycloaryl or a (C₁₀)bicycloaryl.

“Bridging ring” and “bridged ring” as used herein refer to a ring thatis bonded to another ring to form a compound having a bicyclic orpolycyclic structure where two ring atoms that are common to both ringsare not directly bound to each other. Non-exclusive examples of commoncompounds having a bridging ring include borneol, norbornane,7-oxabicyclo[2.2.1]heptane, and the like. One or both rings of thebicyclic system may also comprise heteroatoms.

“Carbamoyl” means the radical —OC(O)NRR′, wherein R and R′ are eachindependently hydrogen or further substituents.

“Carbocycle” means a ring consisting of carbon atoms.

“Carbonyl” means the radical —C(═O)— and/or —C(═O)R, wherein R ishydrogen or a further substituent. It is noted that the carbonyl radicalmay be further substituted with a variety of substituents to formdifferent carbonyl groups including acids, acid halides, aldehydes,amides, esters, and ketones.

“Carboxy” means the radical —C(═O)—O— and/or —C(═O)—OR, wherein R ishydrogen or a further substituent. It is noted that compounds of theinvention containing carboxy moieties may include protected derivativesthereof, i.e., where the oxygen is substituted with a protecting group.Suitable protecting groups for carboxy moieties include benzyl,tert-butyl, and the like.

“Cyano” means the radical —CN.

“Cycloalkyl” means a non-aromatic, saturated or partially unsaturated,monocyclic, bicyclic or polycyclic ring assembly. (C_(X))cycloalkyl and(C_(X-Y))cycloalkyl are typically used where X and Y indicate the numberof carbon atoms in the ring assembly. For example, (C₃₋₁₀)cycloalkylincludes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl,2,5-cyclohexadienyl, bicyclo[2.2.2]octyl, adamantan-1-yl,decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl,2-oxobicyclo[2.2.1]hept-1-yl, and the like. In particular embodiments,“cycloalkyl,” either alone or represented along with another radical,can be a (C₃₋₁₄)cycloalkyl, a (C₃₋₁₀)cycloalkyl, a (C₃₋₇)cycloalkyl, a(C₈₋₁₀)cycloalkyl or a (C₅₋₇)cycloalkyl. Alternatively, “cycloalkyl,”either alone or represented along with another radical, can be a(C₅)cycloalkyl, a (C₆)cycloalkyl, a (C₇)cycloalkyl, a (C₈)cycloalkyl, a(C₉)cycloalkyl or a (C₁₀)cycloalkyl.

“Cycloalkylene” means a divalent, saturated or partially unsaturated,monocyclic, bicyclic or polycyclic ring assembly. (C_(X))cycloalkyleneand (C_(X-Y))cycloalkylene are typically used where X and Y indicate thenumber of carbon atoms in the ring assembly. In particular embodiments,“cycloalkylene,” either alone or represented along with another radical,can be a (C₃₋₁₄)cycloalkylene, a (C₃₋₁₀)cycloalkylene, a(C₃₋₇)cycloalkylene, a (C₈₋₁₀)cycloalkylene or a (C₅₋₇)cycloalkylene.Alternatively, “cycloalkylene,” either alone or represented along withanother radical, can be a (C₅)cycloalkylene, a (C₆)cycloalkylene, a(C₇)cycloalkylene, a (C₈)cycloalkylene, a (C₉)cycloalkylene or a(C₁₀)cycloalkylene.

“Disease” specifically includes any unhealthy condition of an animal orpart thereof and includes an unhealthy condition that may be caused by,or incident to, medical or veterinary therapy applied to that animal,i.e., the “side effects” of such therapy.

“Fused ring” as used herein refers to a ring that is bonded to anotherring to form a compound having a bicyclic structure where the ring atomsthat are common to both rings are directly bound to each other.Non-exclusive examples of common fused rings include decalin,naphthalene, anthracene, phenanthrene, indole, furan, benzofuran,quinoline, and the like. Compounds having fused ring systems may besaturated, partially saturated, carbocyclics, heterocyclics, aromatics,heteroaromatics, and the like.

“Halo” means fluoro, chloro, bromo or iodo.

“Heteroalkyl” means alkyl, as defined in this Application, provided thatone or more of the atoms within the alkyl chain is a heteroatom. Inparticular embodiments, “heteroalkyl,” either alone or represented alongwith another radical, can be a hetero(C₁₋₂₀)alkyl, a hetero(C₁₋₁₅)alkyl,a hetero(C₁₋₁₀)alkyl, a hetero(C₁₋₅)alkyl, a hetero(C₁₋₃)alkyl or ahetero(C₁₋₂)alkyl. Alternatively, “heteroalkyl,” either alone orrepresented along with another radical, can be a hetero(C₁)alkyl, ahetero(C₂)alkyl or a hetero(C₃)alkyl.

“Heteroaryl” means a monocyclic, bicyclic or polycyclic aromatic groupwherein at least one ring atom is a heteroatom and the remaining ringatoms are carbon. Monocyclic heteroaryl groups include, but are notlimited to, cyclic aromatic groups having five or six ring atoms,wherein at least one ring atom is a heteroatom and the remaining ringatoms are carbon. The nitrogen atoms can be optionally quaternerized andthe sulfur atoms can be optionally oxidized. Heteroaryl groups of thisinvention include, but are not limited to, those derived from furan,imidazole, isothiazole, isoxazole, oxadiazole, oxazole,1,2,3-oxadiazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine,pyrroline, thiazole, 1,3,4-thiadiazole, triazole and tetrazole.“Heteroaryl” also includes, but is not limited to, bicyclic or tricyclicrings, wherein the heteroaryl ring is fused to one or two ringsindependently selected from the group consisting of an aryl ring, acycloalkyl ring, a cycloalkenyl ring, and another monocyclic heteroarylor heterocycloalkyl ring. These bicyclic or tricyclic heteroarylsinclude, but are not limited to, those derived from benzo[b]furan,benzo[b]thiophene, benzimidazole, imidazo[4,5-c]pyridine, quinazoline,thieno[2,3-c]pyridine, thieno[3,2-b]pyridine, thieno[2,3-b]pyridine,indolizine, imidazo[1,2a]pyridine, quinoline, isoquinoline, phthalazine,quinoxaline, naphthyridine, quinolizine, indole, isoindole, indazole,indoline, benzoxazole, benzopyrazole, benzothiazole,imidazo[1,5-a]pyridine, pyrazolo[1,5-a]pyridine,imidazo[1,2-a]pyrimidine, imidazo[1,2-c]pyrimidine,imidazo[1,5-a]pyrimidine, imidazo[1,5-c]pyrimidine,pyrrolo[2,3-b]pyridine, pyrrolo[2,3-c]pyridine, pyrrolo[3,2-c]pyridine,pyrrolo[3,2-b]pyridine, pyrrolo[2,3-d]pyrimidine,pyrrolo[3,2-d]pyrimidine, pyrrolo[2,3-b]pyrazine,pyrazolo[1,5-a]pyridine, pyrrolo[1,2-b]pyridazine,pyrrolo[1,2-c]pyrimidine, pyrrolo[1,2-a]pyrimidine,pyrrolo[1,2-a]pyrazine, triazo[1,5-a]pyridine, pteridine, purine,carbazole, acridine, phenazine, phenothiazene, phenoxazine,1,2-dihydropyrrolo[3,2,1-hi]indole, indolizine, pyrido[1,2-a]indole and2(1H)-pyridinone. The bicyclic or tricyclic heteroaryl rings can beattached to the parent molecule through either the heteroaryl groupitself or the aryl, cycloalkyl, cycloalkenyl or heterocycloalkyl groupto which it is fused. The heteroaryl groups of this invention can besubstituted or unsubstituted. In particular embodiments, “heteroaryl,”either alone or represented along with another radical, can be ahetero(C₁₋₁₃)aryl, a hetero(C₂₋₁₃)aryl, a hetero(C₂₋₆)aryl, ahetero(C₃₋₉)aryl or a hetero(C₅₋₉)aryl. Alternatively, “heteroaryl,”either alone or represented along with another radical, can be ahetero(C₃)aryl, a hetero(C₄)aryl, a hetero(C₅)aryl, a hetero(C₆)aryl, ahetero(C₇)aryl, a hetero(C₈)aryl or a hetero(C₉)aryl.

“Heteroatom” refers to an atom that is not a carbon atom. Particularexamples of heteroatoms include, but are not limited to nitrogen,oxygen, and sulfur.

“Heteroatom moiety” includes a moiety where the atom by which the moietyis attached is not a carbon. Examples of heteroatom moieties include—NR—, —N⁺(O⁻)═, —O—, —S— or —S(O)₂—, wherein R is hydrogen or a furthersubstituent.

“Heterobicycloalkyl” means bicycloalkyl, as defined in this Application,provided that one or more of the atoms within the ring is a heteroatom.For example hetero(C₉₋₁₂)bicycloalkyl as used in this applicationincludes, but is not limited to, 3-aza-bicyclo[4.1.0]hept-3-yl,2-aza-bicyclo[3.1.0]hex-2-yl, 3-aza-bicyclo[3.1.0]hex-3-yl, and thelike. In particular embodiments, “heterobicycloalkyl,” either alone orrepresented along with another radical, can be ahetero(C₁₋₁₄)bicycloalkyl, a hetero(C₄₋₁₄)bicycloalkyl, ahetero(C₄₋₉)bicycloalkyl or a hetero(C₅₋₉)bicycloalkyl. Alternatively,“heterobicycloalkyl,” either alone or represented along with anotherradical, can be a hetero(C₅)bicycloalkyl, hetero(C₆)bicycloalkyl,hetero(C₇)bicycloalkyl, hetero(C₈)bicycloalkyl or ahetero(C₉)bicycloalkyl.

“Heterobicycloaryl” means bicycloaryl, as defined in this Application,provided that one or more of the atoms within the ring is a heteroatom.For example, hetero(C₄₋₁₂)bicycloaryl as used in this Applicationincludes, but is not limited to, 2-amino-4-oxo-3,4-dihydropteridin-6-yl,tetrahydroisoquinolinyl, and the like. In particular embodiments,“heterobicycloaryl,” either alone or represented along with anotherradical, can be a hetero(C₁₋₁₄)bicycloaryl, a hetero(C₄₋₁₄)bicycloaryl,a hetero(C₄₋₉)bicycloarylor a hetero(C₅₋₉)bicycloaryl. Alternatively,“heterobicycloaryl,” either alone or represented along with anotherradical, can be a hetero(C₅)bicycloaryl, hetero(C₆)bicycloaryl,hetero(C₇)bicycloaryl, hetero(C₈)bicycloaryl or a hetero(C₉)bicycloaryl.

“Heterocycloalkyl” means cycloalkyl, as defined in this Application,provided that one or more of the atoms forming the ring is a heteroatomselected, independently from N, O, or S, Non-exclusive examples ofheterocycloalkyl include piperidyl, 4-morpholyl, 4-piperazinyl,pyrrolidinyl, perhydropyrrolizinyl, 1,4-diazaperhydroepinyl,1,3-dioxanyl, 1,4-dioxanyl and the like. In particular embodiments,“heterocycloalkyl,” either alone or represented along with anotherradical, can be a hetero(C₁₋₁₃)cycloalkyl, a hetero(C₁₋₉)cycloalkyl, ahetero(C₁₋₆)cycloalkyl, a hetero(C₅₋₉)cycloalkyl or ahetero(C₂₋₆)cycloalkyl. Alternatively, “heterocycloalkyl,” either aloneor represented along with another radical, can be ahetero(C₂)cycloalkyl, a hetero(C₃)cycloalkyl, a hetero(C₄)cycloalkyl, ahetero(C₅)cycloalkyl, a hetero(C₆)cycloalkyl, hetero(C₇)cycloalkyl,hetero(C₈)cycloalkyl or a hetero(C₉)cycloalkyl.

“Heterocycloalkylene” means cycloalkylene, as defined in thisApplication, provided that one or more of the ring member carbon atomsis replaced by a heteroatom. In particular embodiments,“heterocycloalkylene,” either alone or represented along with anotherradical, can be a hetero(C₁₋₁₃)cycloalkylene, ahetero(C₁₋₉)cycloalkylene, a hetero(C₁₋₆)cycloalkylene, ahetero(C₅₋₉)cycloalkylene or a hetero(C₂₋₆)cycloalkylene. Alternatively,“heterocycloalkylene,” either alone or represented along with anotherradical, can be a hetero(C₂)cycloalkylene, a hetero(C₃)cycloalkylene, ahetero(C₄)cycloalkylene, a hetero(C₅)cycloalkylene, ahetero(C₆)cycloalkylene, hetero(C₇)cycloalkylene,hetero(C₈)cycloalkylene or a hetero(C₉)cycloalkylene.

“Hydroxy” means the radical —OH.

“IC₅₀” means the molar concentration of an inhibitor that produces 50%inhibition of the target enzyme.

“Imino” means the radical —CR(═NR′) and/or —C(═NR′)—, wherein R and R′are each independently hydrogen or a further substituent.

“Isomers” means compounds having identical molecular formulae butdiffering in the nature or sequence of bonding of their atoms or in thearrangement of their atoms in space. Isomers that differ in thearrangement of their atoms in space are termed “stereoisomers.”Stereoisomers that are not mirror images of one another are termed“diastereomers” and stereoisomers that are nonsuperimposable mirrorimages are termed “enantiomers” or sometimes “optical isomers.” A carbonatom bonded to four nonidentical substituents is termed a “chiralcenter.” A compound with one chiral center has two enantiomeric forms ofopposite chirality. A mixture of the two enantiomeric forms is termed a“racemic mixture.” A compound that has more than one chiral center has2^(n-1) enantiomeric pairs, where n is the number of chiral centers.Compounds with more than one chiral center may exist as ether anindividual diastereomer or as a mixture of diastereomers, termed a“diastereomeric mixture.” When one chiral center is present astereoisomer may be characterized by the absolute configuration of thatchiral center. Absolute configuration refers to the arrangement in spaceof the substituents attached to the chiral center. Enantiomers arecharacterized by the absolute configuration of their chiral centers anddescribed by the R- and S-sequencing rules of Cahn, Ingold and Prelog.Conventions for stereochemical nomenclature, methods for thedetermination of stereochemistry and the separation of stereoisomers arewell known in the art (e.g., see “Advanced Organic Chemistry”, 4thedition, March, Jerry, John Wiley & Sons, New York, 1992).

“Leaving group” means the group with the meaning conventionallyassociated with it in synthetic organic chemistry, i.e., an atom orgroup displaceable under reaction (e.g., alkylating) conditions.Examples of leaving groups include, but are not limited to, halo (e.g.,F, Cl, Br and I), alkyl (e.g., methyl and ethyl) and sulfonyloxy (e.g.,mesyloxy, ethanesulfonyloxy, benzenesulfonyloxy and tosyloxy),thiomethyl, thienyloxy, dihalophosphinoyloxy, tetrahalophosphoxy,benzyloxy, isopropyloxy, acyloxy, and the like.

“Moiety providing X atom separation” and “linker providing X atomseparation” between two other moieties mean that the chain of atomsdirectly linking the two other moieties is X atoms in length. When X isgiven as a range (e.g., X₁-X₂), then the chain of atoms is at least X₁and not more than X₂ atoms in length. It is understood that the chain ofatoms can be formed from a combination of atoms including, for example,carbon, nitrogen, sulfur and oxygen atoms. Further, each atom canoptionally be bound to one or more substituents, as valencies allow. Inaddition, the chain of atoms can form part of a ring. Accordingly, inone embodiment, a moiety providing X atom separation between two othermoieties (R and R′) can be represented by R-(L)_(X)-R′ where each L isindependently selected from the group consisting of CR″R′″, NR″″, O, S,CO, CS, C═NR″″′, SO, SO₂, and the like, where any two or more of R″,R′″, R″″ and R″″′ can be taken together to form a substituted orunsubstituted ring.

“Nitro” means the radical —NO₂.

“Oxaalkyl” means an alkyl, as defined above, except where one or more ofthe carbon atoms forming the alkyl chain are replaced with oxygen atoms(—O— or —OR, wherein R is hydrogen or a further substituent). Forexample, an oxa(C₁₋₁₀)alkyl refers to a chain comprising between 1 and10 carbons and one or more oxygen atoms.

“Oxoalkyl” means an alkyl, as defined above, except where one or more ofthe carbon atoms forming the alkyl chain are replaced with carbonylgroups (—C(═O)— or —C(═O)—R, wherein R is hydrogen or a furthersubstituent). The carbonyl group may be an aldehyde, ketone, ester,amide, acid or acid halide. For example, an oxo(C₁₋₁₀)alkyl refers to achain comprising between 1 and 10 carbon atoms and one or more carbonylgroups.

“Oxy” means the radical —O— or —OR, wherein R is hydrogen or a furthersubstituent. Accordingly, it is noted that the oxy radical may befurther substituted with a variety of substituents to form different oxygroups including hydroxy, alkoxy, aryloxy, heteroaryloxy or carbonyloxy.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic and neitherbiologically nor otherwise undesirable and includes that which isacceptable for veterinary use as well as human pharmaceutical use.

“Pharmaceutically acceptable salts” means salts of compounds of thepresent invention which are pharmaceutically acceptable, as definedabove, and which possess the desired pharmacological activity. Suchsalts include acid addition salts formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or with organic acids such as aceticacid, propionic acid, hexanoic acid, heptanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, p-chlorobenzenesulfonic acid,2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonicacid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonicacid, 4,4′-methylenebis(3-hydroxy-2-ene-1-carboxylic acid),3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid and the like.

Pharmaceutically acceptable salts also include base addition salts whichmay be formed when acidic protons present are capable of reacting withinorganic or organic bases. Acceptable inorganic bases include sodiumhydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide andcalcium hydroxide. Acceptable organic bases include ethanolamine,diethanolamine, triethanolamine, tromethamine, N-methylglucamine and thelike.

“Polycyclic ring” includes bicyclic and multi-cyclic rings. Theindividual rings comprising the polycyclic ring can be fused, spiro orbridging rings.

“Prodrug” means a compound that is convertible in vivo metabolicallyinto an activator according to the present invention. The prodrug itselfmay or may not also have glucokinase activity. For example, an activatorcomprising a hydroxy group may be administered as an ester that isconverted by hydrolysis in vivo to the hydroxy compound. Suitable estersthat may be converted in vivo into hydroxy compounds include acetates,citrates, lactates, tartrates, malonates, oxalates, salicylates,propionates, succinates, fumarates, maleates,methylene-bis-b-hydroxynaphthoates, gentisates, isethionates,di-p-toluoyltartrates, methanesulfonates, ethanesulfonates,benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates, quinates,esters of amino acids, and the like. Similarly, an activator comprisingan amine group may be administered as an amide that is converted byhydrolysis in vivo to the amine compound.

“Protected derivatives” means derivatives of activators in which areactive site or sites are blocked with protecting groups. Protectedderivatives are useful in the preparation of activators or in themselvesmay be active. A comprehensive list of suitable protecting groups can befound in T. W. Greene, Protecting Groups in Organic Synthesis, 3rdedition, John Wiley & Sons, Inc. 1999.

“Ring” and “ring assembly” means a carbocyclic or a heterocyclic systemand includes aromatic and non-aromatic systems. The system can bemonocyclic, bicyclic or polycyclic. In addition, for bicyclic andpolycyclic systems, the individual rings comprising the polycyclic ringcan be fused, spiro or bridging rings.

“Subject” and “patient” includes humans, non-human mammals (e.g., dogs,cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the like)and non-mammals (e.g., birds, and the like).

“Substituent convertible to hydrogen in vivo” means any group that isconvertible to a hydrogen atom by enzymological or chemical meansincluding, but not limited to, hydrolysis and hydrogenolysis. Examplesinclude hydrolyzable groups, such as acyl groups, groups having anoxycarbonyl group, amino acid residues, peptide residues,o-nitrophenylsulfenyl, trimethylsilyl, tetrahydro-pyranyl,diphenylphosphinyl, and the like. Examples of acyl groups includeformyl, acetyl, trifluoroacetyl, and the like. Examples of groups havingan oxycarbonyl group include ethoxycarbonyl, t-butoxycarbonyl[(CH₃)₃C—OCO—], benzyloxycarbonyl, p-methoxybenzyloxycarbonyl,vinyloxycarbonyl, β-(p-toluenesulfonyl)ethoxycarbonyl, and the like.Examples of suitable amino acid residues include amino acid residues perse and amino acid residues that are protected with a protecting group.Suitable amino acid residues include, but are not limited to, residuesof Gly (glycine), Ala (alanine; CH₃CH(NH₂)CO—), Arg (arginine), Asn(asparagine), Asp (aspartic acid), Cys (cysteine), Glu (glutamic acid),His (histidine), Ile (isoleucine), Leu (leucine; (CH₃)₂CHCH₂CH(NH₂)CO—),Lys (lysine), Met (methionine), Phe (phenylalanine), Pro (proline), Ser(serine), Thr (threonine), Trp (tryptophan), Tyr (tyrosine), Val(valine), Nva (norvaline), Hse (homoserine), 4-Hyp (4-hydroxyproline),5-Hyl (5-hydroxylysine), Orn (ornithine) and β-Ala. Examples of suitableprotecting groups include those typically employed in peptide synthesis,including acyl groups (such as formyl and acetyl), arylmethyloxycarbonylgroups (such as benzyloxycarbonyl and p-nitrobenzyloxycarbonyl),t-butoxycarbonyl groups [(CH₃)₃C—OCO—], and the like. Suitable peptideresidues include peptide residues comprising two to five, and optionallytwo to three, of the aforesaid amino acid residues. Examples of suchpeptide residues include, but are not limited to, residues of suchpeptides as Ala-Ala [CH₃CH(NH₂)CO—NHCH(CH₃)CO—], Gly-Phe, Nva-Nva,Ala-Phe, Gly-Gly, Gly-Gly-Gly, Ala-Met, Met-Met, Leu-Met and Ala-Leu.The residues of these amino acids or peptides can be present instereochemical configurations of the D-form, the L-form or mixturesthereof. In addition, the amino acid or peptide residue may have anasymmetric carbon atom. Examples of suitable amino acid residues havingan asymmetric carbon atom include residues of Ala, Leu, Phe, Trp, Nva,Val, Met, Ser, Lys, Thr and Tyr. Peptide residues having an asymmetriccarbon atom include peptide residues having one or more constituentamino acid residues having an asymmetric carbon atom. Examples ofsuitable amino acid protecting groups include those typically employedin peptide synthesis, including acyl groups (such as formyl and acetyl),arylmethyloxycarbonyl groups (such as benzyloxycarbonyl andp-nitrobenzyloxycarbonyl), t-butoxycarbonyl groups [(CH₃)₃C—OCO—], andthe like. Other examples of substituents “convertible to hydrogen invivo” include reductively eliminable hydrogenolyzable groups. Examplesof suitable reductively eliminable hydrogenolyzable groups include, butare not limited to, arylsulfonyl groups (such as o-toluenesulfonyl);methyl groups substituted with phenyl or benzyloxy (such as benzyl,trityl and benzyloxymethyl); arylmethoxycarbonyl groups (such asbenzyloxycarbonyl and o-methoxy-benzyloxycarbonyl); andhalogenoethoxycarbonyl groups (such as β,β,β-trichloroethoxycarbonyl andβ-iodoethoxycarbonyl).

“Substituted or unsubstituted” means that a given moiety may consist ofonly hydrogen substituents through available valencies (unsubstituted)or may further comprise one or more non-hydrogen substituents throughavailable valencies (substituted) that are not otherwise specified bythe name of the given moiety. For example, isopropyl is an example of anethylene moiety that is substituted by —CH₃. In general, a non-hydrogensubstituent may be any substituent that may be bound to an atom of thegiven moiety that is specified to be substituted. Examples ofsubstituents include, but are not limited to, aldehyde, alicyclic,aliphatic, (C₁₋₁₀)alkyl, alkylene, alkylidene, amide, amino, aminoalkyl,aromatic, aryl, bicycloalkyl, bicycloaryl, carbamoyl, carbocyclyl,carboxyl, carbonyl group, cycloalkyl, cycloalkylene, ester, halo,heterobicycloalkyl, heterocycloalkylene, heteroaryl, heterobicycloaryl,heterocycloalkyl, oxo, hydroxy, iminoketone, ketone, nitro, oxaalkyl,and oxoalkyl moieties, each of which may optionally also be substitutedor unsubstituted. In one particular embodiment, examples of substituentsinclude, but are not limited to, hydrogen, halo, nitro, cyano, thio,oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino,(C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,(C₁₋₁₀)azaalkyl, imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl. In addition, the substituent is itselfoptionally substituted by a further substituent. In one particularembodiment, examples of the further substituent include, but are notlimited to, hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy,carbonyl, oxycarbonyl, aminocarbonyl, amino, (C₁₋₁₀)alkylamino,sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl.

“Sulfinyl” means the radical —SO— and/or —SO—R, wherein R is hydrogen ora further substituent. It is noted that the sulfinyl radical may befurther substituted with a variety of substituents to form differentsulfinyl groups including sulfinic acids, sulfinamides, sulfinyl esters,and sulfoxides.

“Sulfonyl” means the radical —SO₂— and/or —SO₂—R, wherein R is hydrogenor a further substituent. It is noted that the sulfonyl radical may befurther substituted with a variety of substituents to form differentsulfonyl groups including sulfonic acids, sulfonamides, sulfonateesters, and sulfones.

“Therapeutically effective amount” means that amount which, whenadministered to an animal for treating a disease, is sufficient toeffect such treatment for the disease.

“Thio” denotes replacement of an oxygen by a sulfur and includes, but isnot limited to, —SR, —S— and ═S containing groups.

“Thioalkyl” means an alkyl, as defined above, except where one or moreof the carbon atoms forming the alkyl chain are replaced with sulfuratoms (—S— or —S—R, wherein R is hydrogen or a further substituent). Forexample, a thio(C₁₋₁₀)alkyl refers to a chain comprising between 1 and10 carbons and one or more sulfur atoms.

“Thiocarbonyl” means the radical —C(═S)— and/or —C(═S)—R, wherein R ishydrogen or a further substituent. It is noted that the thiocarbonylradical may be further substituted with a variety of substituents toform different thiocarbonyl groups including thioacids, thioamides,thioesters, and thioketones.

“Treatment” or “treating” means any administration of a compound of thepresent invention and includes:

(1) preventing the disease from occurring in an animal which may bepredisposed to the disease but does not yet experience or display thepathology or symptomatology of the disease,

(2) inhibiting the disease in an animal that is experiencing ordisplaying the pathology or symptomatology of the diseased (i.e.,arresting further development of the pathology and/or symptomatology),or

(3) ameliorating the disease in an animal that is experiencing ordisplaying the pathology or symptomatology of the diseased (i.e.,reversing the pathology and/or symptomatology).

It is noted in regard to all of the definitions provided herein that thedefinitions should be interpreted as being open ended in the sense thatfurther substituents beyond those specified may be included. Hence, a C₁alkyl indicates that there is one carbon atom but does not indicate whatare the substituents on the carbon atom. Hence, a (C₁)alkyl comprisesmethyl (i.e., —CH₃) as well as —CRR′R″ where R, R′, and R″ may eachindependently be hydrogen or a further substituent where the atomattached to the carbon is a heteroatom or cyano. Hence, CF₃, CH₂OH andCH₂CN, for example, are all (C₁)alkyls. Similarly, terms such asalkylamino and the like comprise dialkylamino and the like.

A compound having a formula that is represented with a dashed bond isintended to include the formulae optionally having zero, one or moredouble bonds, as exemplified and shown below:

In addition, atoms making up the compounds of the present invention areintended to include all isotopic forms of such atoms. Isotopes, as usedherein, include those atoms having the same atomic number but differentmass numbers. By way of general example and without limitation, isotopesof hydrogen include tritium and deuterium, and isotopes of carboninclude ¹³C and ¹⁴C.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds that may be used to activatehexokinases and, in particular, glucokinase (referred to herein as“GK”). The present invention also relates to pharmaceuticalcompositions, kits and articles of manufacture comprising suchcompounds. In addition, the present invention relates to methods andintermediates useful for making the compounds. Further, the presentinvention relates to methods of using said compounds. It is noted thatthe compounds of the present invention may also possess activity forother hexokinases family members and thus may be used to address diseasestates associated with these other family members.

Glucokinase Activators

In one of its aspects, the present invention relates to compounds thatare useful as glucokinase activators. In one embodiment, glucokinaseactivators of the present invention comprise:

or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceuticallyacceptable salt or prodrug thereof, wherein

-   -   L is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between Q and the ring to which L is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur;    -   Q is selected from the group consisting of C(═O), C(═S),        C(═NR₆), SO and SO₂;    -   U, V, W, X, Y and Z are each independently selected from the        group consisting of CR₄R₅, NR₆, C(═O), C(═S) and C(═NR₆);    -   R₁ is selected from the group consisting of        hetero(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, heteroaryl,        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen and a        substituent convertible to hydrogen in vivo;    -   each R₄ and R₅ is independently selected from the group        consisting of hydrogen, halo, nitro, cyano, thio, hydroxy,        alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or any two R₄ and R₅ are taken together to form a ring, with the        proviso that R₅ is absent when the atom to which it is bound        forms part of a double bond; and    -   each R₆ is independently selected from the group consisting of        hydrogen, oxy, hydroxy, carbonyloxy, alkoxy, aryloxy,        heteroaryloxy, carbonyl, oxycarbonyl, amino, (C₁₋₁₀)alkylamino,        sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₄ or R₅ and R₆ are taken        together to form a ring, with the proviso that R₆ is absent when        the atom to which it is bound forms part of a double bond.

In one particular variation of the above embodiment, R₁ is not2-hydroxycarbonyl-3,3,6-trimethyl-1-azabicyclo[3.2.0]heptan-7-on-6-ylwhen U and Z are N and V, W, X and Y are C.

In another embodiment, glucokinase activators of the present inventioncomprise:

wherein

-   -   p is selected from the group consisting of 1, 2, 3, 4, 5 and 6;        and    -   R₃ and R₃′ are each independently selected from the group        consisting of hydrogen, carbonyl, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ and R₃′ are taken together to form a ring.

In one particular variation of the above embodiment, R₁ is not2-hydroxycarbonyl-3,3,6-trimethyl-1-azabicyclo[3.2.0]heptan-7-on-6-ylwhen U and Z are N and V, W, X and Y are C.

In still another embodiment, glucokinase activators of the presentinvention comprise:

wherein

-   -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In one particular variation of the above embodiment, R₁ is not2-hydroxycarbonyl-3,3,6-trimethyl-1-azabicyclo[3.2.0]heptan-7-on-6-ylwhen U and Z are N and V, W, X and Y are C.

In yet another embodiment, glucokinase activators of the presentinvention comprise:

wherein

-   -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In another embodiment, glucokinase activators of the present inventioncomprise:

wherein

-   -   n is selected from the group consisting of 0, 1, 2, 3, 4 and 5;        and    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In a further embodiment, glucokinase activators of the present inventioncomprise:

wherein

-   -   m is selected from the group consisting of 0, 1, 2, 3 and 4; and    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In still a further embodiment, glucokinase activators of the presentinvention comprise:

wherein

-   -   m is selected from the group consisting of 0, 1, 2, 3 and 4; and    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In yet a further embodiment, glucokinase activators of the presentinvention comprise:

wherein

-   -   m is selected from the group consisting of 0, 1, 2, 3 and 4; and    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In another embodiment, glucokinase activators of the present inventioncomprise:

wherein

-   -   m is selected from the group consisting of 0, 1, 2, 3 and 4; and    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In still another embodiment, glucokinase activators of the presentinvention comprise:

wherein

-   -   l is selected from the group consisting of 0, 1, 2 and 3; and    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In yet another embodiment, glucokinase activators of the presentinvention comprise:

wherein

-   -   l is selected from the group consisting of 0, 1, 2 and 3; and    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In a further embodiment, glucokinase activators of the present inventioncomprise:

wherein

-   -   l is selected from the group consisting of 0, 1, 2 and 3; and    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In still a further embodiment, glucokinase activators of the presentinvention comprise:

wherein

-   -   l is selected from the group consisting of 0, 1, 2 and 3; and    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In yet a further embodiment, glucokinase activators of the presentinvention comprise:

wherein

-   -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In another embodiment, glucokinase activators of the present inventioncomprise:

wherein

-   -   m is selected from the group consisting of 0, 1, 2, 3 and 4; and    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In still another embodiment, glucokinase activators of the presentinvention comprise:

wherein

-   -   l is selected from the group consisting of 0, 1, 2 and 3; and    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In yet another embodiment, glucokinase activators of the presentinvention comprise:

wherein

-   -   l is selected from the group consisting of 0, 1, 2 and 3; and    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In a further embodiment, glucokinase activators of the present inventioncomprise:

wherein

-   -   l is selected from the group consisting of 0, 1, 2 and 3; and    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In still a further embodiment, glucokinase activators of the presentinvention comprise:

wherein

-   -   l is selected from the group consisting of 0, 1, 2 and 3; and    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In yet a further embodiment, glucokinase activators of the presentinvention comprise:

wherein

-   -   k is selected from the group consisting of 0, 1 and 2; and    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In another embodiment, glucokinase activators of the present inventioncomprise:

wherein

-   -   k is selected from the group consisting of 0, 1 and 2; and    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In still another embodiment, glucokinase activators of the presentinvention comprise:

wherein

-   -   k is selected from the group consisting of 0, 1 and 2; and    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In yet another embodiment, glucokinase activators of the presentinvention comprise:

wherein

-   -   k is selected from the group consisting of 0, 1 and 2; and    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In a further embodiment, glucokinase activators of the present inventioncomprise:

wherein

-   -   k is selected from the group consisting of 0, 1 and 2; and    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In still a further embodiment, glucokinase activators of the presentinvention comprise:

wherein

-   -   k is selected from the group consisting of 0, 1 and 2; and    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In yet a further embodiment, glucokinase activators of the presentinvention comprise:

wherein

-   -   k is selected from the group consisting of 0, 1 and 2; and    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In another embodiment, glucokinase activators of the present inventioncomprise:

wherein

-   -   k is selected from the group consisting of 0, 1 and 2; and    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In still another embodiment, glucokinase activators of the presentinvention comprise:

wherein

-   -   k is selected from the group consisting of 0, 1 and 2; and    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In yet another embodiment, glucokinase activators of the presentinvention comprise:

wherein

-   -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In a further embodiment, glucokinase activators of the present inventioncomprise:

wherein

-   -   l is selected from the group consisting of 0, 1, 2 and 3; and    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In still a further embodiment, glucokinase activators of the presentinvention comprise:

wherein

-   -   l is selected from the group consisting of 0, 1, 2 and 3; and    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In yet a further embodiment, glucokinase activators of the presentinvention comprise:

wherein

-   -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In another embodiment, glucokinase activators of the present inventioncomprise:

wherein

-   -   m is selected from the group consisting of 0, 1, 2, 3 and 4; and    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

Particular examples of compounds according to the present inventioninclude, but are not limited to:

-   2-(2H-indazol-2-yl)-4-methyl-N-(thiazol-2-yl)pentanamide;-   2-(5-fluoro-2H-indazol-2-yl)-4-methyl-N-(thiazol-2-yl)pentanamide;-   4-methyl-2-(6-nitro-2H-indazol-2-yl)-N-(thiazol-2-yl)pentanamide;-   4-methyl-2-(6-(methylsulfonyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)pentanamide;-   2-(5-methoxy-2H-indazol-2-yl)-4-methyl-N-(thiazol-2-yl)pentanamide;-   2-(5-hydroxy-2H-indazol-2-yl)-4-methyl-N-(thiazol-2-yl)pentanamide;-   4-methyl-2-(3-methyl-2H-indazol-2-yl)-N-(thiazol-2-yl)pentanamide;-   2-(5-fluoro-3-methyl-2H-indazol-2-yl)-4-methyl-N-(thiazol-2-yl)pentanamide;-   3-cyclohexyl-2-(1-iminoisoindolin-2-yl)-N-(thiazol-2-yl)propanamide;-   3-cyclohexyl-2-(6-fluoro-1-iminoisoindolin-2-yl)-N-(thiazol-2-yl)propanamide;-   2-(1,3-dioxoisoindolin-2-yl)-4-methyl-N-(thiazol-2-yl)pentanamide;-   2-(1,3-dioxoisoindolin-2-yl)-4-methyl-N-(pyridin-2-yl)pentanamide;-   2-(3-amino-2H-indazol-2-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;-   2-(3-amino-5-fluoro-2H-indazol-2-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;-   2-(3-amino-5-(methylsulfonyl)-2H-indazol-2-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;-   2-(3-amino-5-(N-methylsulfamoyl)-2H-indazol-2-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;-   2-(3-amino-2H-pyrazolo[4,3-b]pyridin-2-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;-   2-(3-amino-2H-pyrazolo[4,3-c]pyridin-2-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;-   2-(3-amino-2H-pyrazolo[3,4-c]pyridin-2-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;-   2-(3-amino-2H-pyrazolo[3,4-b]pyridin-2-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;-   2-(3-amino-2H-pyrazolo[4,3-b]pyrazin-2-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;-   2-(3-amino-2H-pyrazolo[3,4-d]pyrimidin-2-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;-   2-(3-amino-2H-pyrazolo[4,3-d]pyrimidin-2-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;-   2-(3-amino-4-oxo-4,5-dihydro-2H-pyrazolo[4,3-c]pyridin-2-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;-   2-(3-amino-4-oxo-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-2-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;-   2-(3-amino-5-(methylsulfonyl)-2H-indazol-2-yl)-3-cyclohexyl-N-(pyridin-2-yl)propanamide;-   3-cyclohexyl-2-(1-imino-6-(methylsulfonyl)isoindolin-2-yl)-N-(thiazol-2-yl)propanamide;-   3-cyclohexyl-2-(1-imino-6-(N-methylsulfamoyl)isoindolin-2-yl)-N-(thiazol-2-yl)propanamide;-   3-cyclohexyl-2-(7-imino-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)-N-(thiazol-2-yl)propanamide;    and-   3-cyclohexyl-2-(3-imino-1H-pyrrolo[3,4-c]pyridin-2(3H)-yl)-N-(thiazol-2-yl)propanamide.

Further, particular examples of compounds according to the presentinvention include, but are not limited to:

-   2-(2H-indazol-2-yl)-4-methyl-N-(thiazol-2-yl)pentanamide;-   4-methyl-2-(6-nitro-2H-indazol-2-yl)-N-(thiazol-2-yl)pentanamide;-   2-(5-hydroxy-2H-indazol-2-yl)-4-methyl-N-(thiazol-2-yl)pentanamide;-   4-methyl-2-(3-methyl-2H-indazol-2-yl)-N-(thiazol-2-yl)pentanamide;-   3-cyclohexyl-2-(1-iminoisoindolin-2-yl)-N-(thiazol-2-yl)propanamide;-   3-cyclohexyl-2-(6-fluoro-1-iminoisoindolin-2-yl)-N-(thiazol-2-yl)propanamide;-   2-(1,3-dioxoisoindolin-2-yl)-4-methyl-N-(thiazol-2-yl)pentanamide;-   2-(1,3-dioxoisoindolin-2-yl)-4-methyl-N-(pyridin-2-yl)pentanamide.

Still further, particular examples of compounds according to the presentinvention include, but are not limited to:

-   2-(2H-indazol-2-yl)-4-methyl-N-(thiazol-2-yl)pentanamide;-   2-(5-hydroxy-2H-indazol-2-yl)-4-methyl-N-(thiazol-2-yl)pentanamide;-   3-cyclohexyl-2-(1-iminoisoindolin-2-yl)-N-(thiazol-2-yl)propanamide;-   3-cyclohexyl-2-(6-fluoro-1-iminoisoindolin-2-yl)-N-(thiazol-2-yl)propanamide;-   2-(1,3-dioxoisoindolin-2-yl)-4-methyl-N-(thiazol-2-yl)pentanamide;    and-   2-(1,3-dioxoisoindolin-2-yl)-4-methyl-N-(pyridin-2-yl)pentanamide.

Particular examples of compounds according to the present invention alsoinclude, but are not limited to:

-   4-methyl-2-(6-nitro-2H-indazol-2-yl)-N-(thiazol-2-yl)pentanamide;-   4-methyl-2-(3-methyl-2H-indazol-2-yl)-N-(thiazol-2-yl)pentanamide;-   3-cyclohexyl-2-(1-iminoisoindolin-2-yl)-N-(thiazol-2-yl)propanamide;    and-   2-(1,3-dioxoisoindolin-2-yl)-4-methyl-N-(thiazol-2-yl)pentanamide.

In addition, particular examples of compounds according to the presentinvention include, but are not limited to:

-   3-cyclohexyl-2-(1-iminoisoindolin-2-yl)-N-(thiazol-2-yl)propanamide;    and-   2-(1,3-dioxoisoindolin-2-yl)-4-methyl-N-(thiazol-2-yl)pentanamide.

In another of its aspects, the present invention relates to methods ofmaking compounds that are useful as glucokinase activators. In oneembodiment, the methods comprise the steps of:

reacting a compound having the formula

with a compound having the formula

under conditions that form a first reaction product having the formula

reacting the first reaction product with a compound having the formulaNHR₁R₂

under conditions that form a second reaction product having the formula

wherein

-   -   p is selected from the group consisting of 1, 2, 3, 4, 5 and 6;    -   Q is selected from the group consisting of C(═O), C(═S),        C(═NR₆), SO and SO₂;    -   V, W, X and Y are each independently selected from the group        consisting of CR₄R₅, NR₆, C(═O), C(═S) and C(═NR₆);    -   R₁ is selected from the group consisting of        hetero(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, heteroaryl,        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen and a        substituent convertible to hydrogen in vivo;    -   R₃ and R₃′ are each independently selected from the group        consisting of hydrogen, carbonyl, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ and R₃′ are taken together to form a ring;    -   each R₄ and R₅ is independently selected from the group        consisting of hydrogen, halo, nitro, cyano, thio, hydroxy,        alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or any two R₄ and R₅ are taken together to form a ring, with the        proviso that R₅ is absent when the atom to which it is bound        forms part of a double bond;    -   each R₆ is independently selected from the group consisting of        hydrogen, oxy, hydroxy, carbonyloxy, alkoxy, aryloxy,        heteroaryloxy, carbonyl, oxycarbonyl, amino, (C₁₋₁₀)alkylamino,        sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₄ or R₅ and R₆ are taken        together to form a ring, with the proviso that R₆ is absent when        the atom to which it is bound forms part of a double bond; and    -   LG₁ and LG₂ are each independently a leaving group.

In another embodiment, the methods comprise the steps of:

reacting a compound having the formula

with a compound having the formulaNHR₁R₂

under conditions that form a first reaction product having the formula

reacting the first reaction product with a compound having the formula

under conditions that form a second reaction product comprising offormula

wherein

-   -   p is selected from the group consisting of 1, 2, 3, 4, 5 and 6;    -   Q is selected from the group consisting of C(═O), C(═S),        C(═NR₆), SO and SO₂;    -   V, W, X and Y are each independently selected from the group        consisting of CR₄R₅, NR₆, C(═O), C(═S) and C(═NR₆);    -   R₁ is selected from the group consisting of        hetero(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, heteroaryl,        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen and a        substituent convertible to hydrogen in vivo;    -   R₃ and R₃′ are each independently selected from the group        consisting of hydrogen, carbonyl, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ and R₃′ are taken together to form a ring;    -   each R₄ and R₅ is independently selected from the group        consisting of hydrogen, halo, nitro, cyano, thio, hydroxy,        alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or any two R₄ and R₅ are taken together to form a ring, with the        proviso that R₅ is absent when the atom to which it is bound        forms part of a double bond;    -   each R₆ is independently selected from the group consisting of        hydrogen, oxy, hydroxy, carbonyloxy, alkoxy, aryloxy,        heteroaryloxy, carbonyl, oxycarbonyl, amino, (C₁₋₁₀)alkylamino,        sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₄ or R₅ and R₆ are taken        together to form a ring, with the proviso that R₆ is absent when        the atom to which it is bound forms part of a double bond;    -   PG is a protecting group; and    -   LG₂ and LG₃ are each independently a leaving group.

In still another embodiment, the methods comprise the steps of:

reacting a compound having the formula

with a compound having the formula

under conditions that form a first reaction product having the formula

reacting the first reaction product with a compound having the formulaNHR₁R₂

under conditions that form a second reaction product comprising offormula

wherein

-   -   p is selected from the group consisting of 1, 2, 3, 4, 5 and 6;    -   Q is selected from the group consisting of C(═O), C(═S),        C(═NR₆), SO and SO₂;    -   V, W, X and Y are each independently selected from the group        consisting of CR₄R₅, NR₆, C(═O), C(═S) and C(═NR₆);    -   R₁ is selected from the group consisting of        hetero(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, heteroaryl,        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen and a        substituent convertible to hydrogen in vivo;    -   R₃ and R₃′ are each independently selected from the group        consisting of hydrogen, carbonyl, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ and R₃′ are taken together to form a ring;    -   each R₄ and R₅ is independently selected from the group        consisting of hydrogen, halo, nitro, cyano, thio, hydroxy,        alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or any two R₄ and R₅ are taken together to form a ring, with the        proviso that R₅ is absent when the atom to which it is bound        forms part of a double bond;    -   each R₆ is independently selected from the group consisting of        hydrogen, oxy, hydroxy, carbonyloxy, alkoxy, aryloxy,        heteroaryloxy, carbonyl, oxycarbonyl, amino, (C₁₋₁₀)alkylamino,        sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₄ or R₅ and R₆ are taken        together to form a ring, with the proviso that R₆ is absent when        the atom to which it is bound forms part of a double bond; and    -   LG₂ is a leaving group.

In still another of its aspects, the present invention relates tointermediates that are useful in making glucokinase activators. In oneembodiment, the intermediates comprise

wherein

-   -   p is selected from the group consisting of 1, 2, 3, 4, 5 and 6;    -   Q is selected from the group consisting of C(═O), C(═S),        C(═NR₆), SO and SO₂;    -   V, W, X and Y are each independently selected from the group        consisting of CR₄R₅, NR₆, C(═O), C(═S) and C(═NR₆);    -   R₃ and R₃′ are each independently selected from the group        consisting of hydrogen, carbonyl, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ and R₃′ are taken together to form a ring;    -   each R₄ and R₅ is independently selected from the group        consisting of hydrogen, halo, nitro, cyano, thio, hydroxy,        alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or any two R₄ and R₅ are taken together to form a ring, with the        proviso that R₅ is absent when the atom to which it is bound        forms part of a double bond;    -   each R₆ is independently selected from the group consisting of        hydrogen, oxy, hydroxy, carbonyloxy, alkoxy, aryloxy,        heteroaryloxy, carbonyl, oxycarbonyl, amino, (C₁₋₁₀)alkylamino,        sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₄ or R₅ and R₆ are taken        together to form a ring, with the proviso that R₆ is absent when        the atom to which it is bound forms part of a double bond; and    -   LG₂ is a leaving group.

In another embodiment, the intermediates comprise

wherein

-   -   p is selected from the group consisting of 1, 2, 3, 4, 5 and 6;    -   Q is selected from the group consisting of C(═O), C(═S),        C(═NR₆), SO and SO₂;    -   R₁ is selected from the group consisting of        hetero(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, heteroaryl,        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen and a        substituent convertible to hydrogen in vivo;    -   R₃ and R₃′ are each independently selected from the group        consisting of hydrogen, carbonyl, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ and R₃′ are taken together to form a ring; and    -   each R₆ is independently selected from the group consisting of        hydrogen, oxy, hydroxy, carbonyloxy, alkoxy, aryloxy,        heteroaryloxy, carbonyl, oxycarbonyl, amino, (C₁₋₁₀)alkylamino,        sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₄ or R₅ and R₆ are taken        together to form a ring, with the proviso that R₆ is absent when        the atom to which it is bound forms part of a double bond.

In still another embodiment, the intermediates comprise

wherein

-   -   p is selected from the group consisting of 1, 2, 3, 4, 5 and 6;    -   Q is selected from the group consisting of C(═O), C(═S),        C(═NR₆), SO and SO₂;    -   V, W, X and Y are each independently selected from the group        consisting of CR₄R₅, NR₆,    -   R₃ and R₃′ are each independently selected from the group        consisting of hydrogen, carbonyl, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ and R₃′ are taken together to form a ring;    -   each R₄ and R₅ is independently selected from the group        consisting of hydrogen, halo, nitro, cyano, thio, hydroxy,        alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or any two R₄ and R₅ are taken together to form a ring, with the        proviso that R₅ is absent when the atom to which it is bound        forms part of a double bond;    -   each R₆ is independently selected from the group consisting of        hydrogen, oxy, hydroxy, carbonyloxy, alkoxy, aryloxy,        heteroaryloxy, carbonyl, oxycarbonyl, amino, (C₁₋₁₀)alkylamino,        sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₄ or R₅ and R₆ are taken        together to form a ring, with the proviso that R₆ is absent when        the atom to which it is bound forms part of a double bond; and    -   LG₂ is a leaving group.

In one variation of each of the above embodiments and variations, L is

-   -   p is selected from the group consisting of 1, 2, 3, 4, 5 and 6;        and    -   R₃ and R₃′ are each independently selected from the group        consisting of hydrogen, carbonyl, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ and R₃′ are taken together to form a ring.

In another variation of each of the above embodiments and variations, pis selected from the group consisting of 1, 2 and 3. In still anothervariation, p is 1.

In yet another variation of each of the above embodiments andvariations, L is CHR₃ and R₃ is selected from the group consisting ofhydrogen, carbonyl, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,aryl, heteroaryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted.

In one variation of each of the above embodiments and variations, Q isC(═O). In another variation of each of the above embodiments andvariations, Q is C(═S). In still another variation of each of the aboveembodiments and variations, Q is C(═NR₆)—In yet another variation ofeach of the above embodiments and variations, Q is SO. In a furthervariation of each of the above embodiments and variations, Q is SO₂.

In one variation of each of the above embodiments and variations, U isselected from the group consisting of N, CH₂ and CO.

In another variation of each of the above embodiments and variations, Vis selected from the group consisting of N and CH.

In still another variation of each of the above embodiments andvariations, W is selected from the group consisting of N, CH, C(NO₂) andC(SO₂CH₃).

In yet another variation of each of the above embodiments andvariations, X is selected from the group consisting of N, NH, CH, CF,C(OCH₃), C(OH), C(SO₂CH₃) and C(SO₂NHCH₃).

In a further variation of each of the above embodiments and variations,Y is selected from the group consisting of N, CH and CO.

In still a further variation of each of the above embodiments andvariations, Z is selected from the group consisting of C(CH₃), C(NH₂),C(═NH) and CO.

In one variation of each of the above embodiments and variations, k is0. In another variation, k is 1.

In one variation of each of the above embodiments and variations, l is0. In another variation, l is 1.

In one variation of each of the above embodiments and variations, m is0. In another variation, m is 1.

In one variation of each of the above embodiments and variations, n is0. In another variation, n is 1. In a further variation, n is 2.

In one variation of each of the above embodiments and variations, R₁ isa substituted or unsubstituted hetero(C₃₋₁₂)cycloalkyl.

In another variation of each of the above embodiments and variations, R₁is a substituted or unsubstituted heteroaryl.

In still another variation of each of the above embodiments andvariations, R₁ is selected from the group consisting of furanyl,thiophenyl, 2H-pyrrolyl, 1,3-dioxoianyl, oxazolyl, thiazolyl,imidazolyl, 2-imidazolinyl, pyrazolyl, 2-pyrazolinyl, isoxazolyl,isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl,2H-pyranyl, 4H-pyranyl, pyridinyl, 1,4-dioxanyl, morpholinyl,1,4-dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl,1,3,5-triazinyl, 1,3,5-trithianyl, 3-H-indolyl, benzo[b]furanyl,benzo[b]thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl,purinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl,quinuclidinyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl,each substituted or unsubstituted.

In yet another variation of each of the above embodiments andvariations, R₁ is selected from the group consisting of oxazolyl,thiazolyl, imidazolyl, 2-imidazolinyl, pyrazolyl, isoxazolyl,isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1H-indazolyl,benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl,cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,1,8-naphthyridinyl, and pteridinyl, each substituted or unsubstituted.

In a further variation of each of the above embodiments and variations,R₁ is a substituted or unsubstituted thiazolyl.

In still a further variation of each of the above embodiments andvariations, R₁ is a substituted or unsubstituted pyridinyl.

In one variation of each of the above embodiments and variations, R₂ ishydrogen.

In one variation of each of the above embodiments and variations, R₃′ isselected from the group consisting of hydrogen, halo, and substituted orunsubstituted (C₁₋₃)alkyl. In another variation, R₃′ is hydrogen.

In one variation of each of the above embodiments and variations, R₃ isselected from the group consisting of (C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl,cycloalkyl(C₁₋₅)alkyl, heterocycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₅)alkyl, andheteroaryl(C₁₋₅)alkyl, each substituted or unsubstituted.

In another variation of each of the above embodiments and variations, R₃is selected from the group consisting of isobutyl, methoxybutyl,methoxypentyl, cyclohexylmethyl, cyclopentylmethyl, cyclopropylmethyl,benzyl, imidazolylmethyl, pyridinylmethyl, pyrrolidinylmethyl, andpiperidinylmethyl, each substituted or unsubstituted.

In still another variation of each of the above embodiments andvariations, R₃ is selected from the group consisting of isobutyl andcyclohexylmethyl, each substituted or unsubstituted.

In one variation of each of the above embodiments and variations, atleast one R₄ is selected from the group consisting of hydrogen, halo,hydroxy, amino, nitro, (C₁₋₃)alkoxy, (C₁₋₃)alkylsulfonyl, aminosulfonyland (C₁₋₁₀)alkyl, each substituted or unsubstituted.

In another variation of each of the above embodiments and variations, atleast one R₄ is selected from the group consisting of amino and(C₁₋₁₀)alkyl, each substituted or unsubstituted.

In still another variation of each of the above embodiments andvariations, at least one R₄ is selected from the group consisting ofhydrogen, halogen and (C₁₋₃)alkylsulfonyl, each substituted orunsubstituted.

In yet another variation of each of the above embodiments andvariations, at least one R₄ is selected from the group consisting of H,F, CH₃, NH₂, SO₂CH₃, SO₂NHCH₃, NO₂, OCH₃ and OH, each substituted orunsubstituted.

In one variation of each of the above embodiments and variations, atleast one R₅ is selected from the group consisting of hydrogen, halogenand (C₁₋₃)alkylsulfonyl, each substituted or unsubstituted. In anothervariation, at least one R₅ is hydrogen. In still another variation, atleast one R₅ is halo.

In one variation of each of the above embodiments and variations, atleast one R₆ is selected from the group consisting of hydrogen,(C₁₋₁₀)alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₁₀)alkyl, (C₉₋₁₂)bicycloaryl,hetero(C₈₋₁₂)bicycloaryl, each substituted or unsubstituted.

It is noted that the compounds of the present invention may be in theform of a pharmaceutically acceptable salt, biohydrolyzable ester,biohydrolyzable amide, biohydrolyzable carbamate, solvate, hydrate orprodrug thereof. For example, the compound optionally comprises asubstituent that is convertible in vivo to a different substituent suchas hydrogen.

It is further noted that the compound may be present in a mixture ofstereoisomers, or the compound may comprise a single stereoisomer.

In another of its aspects, there is provided a pharmaceuticalcomposition comprising as an active ingredient a compound according toany one of the above embodiments and variations. In one particularvariation, the composition is a solid formulation adapted for oraladministration. In another particular variation, the composition is aliquid formulation adapted for oral administration. In yet anotherparticular variation, the composition is a tablet. In still anotherparticular variation, the composition is a liquid formulation adaptedfor parenteral administration.

The present invention also provides a pharmaceutical compositioncomprising a compound according to any one of the above embodiments andvariations, wherein the composition is adapted for administration by aroute selected from the group consisting of orally, parenterally,intraperitoneally, intravenously, intraarterially, transdermally,sublingually, intramuscularly, rectally, transbuccally, intranasally,liposomally, via inhalation, vaginally, intraoccularly, via localdelivery (for example by catheter or stent), subcutaneously,intraadiposally, intraarticularly, and intrathecally.

In yet another of its aspects, there is provided a kit comprising acompound of any one of the above embodiments and variations; andinstructions which comprise one or more forms of information selectedfrom the group consisting of indicating a disease state for which thecomposition is to be administered, storage information for thecomposition, dosing information and instructions regarding how toadminister the composition. In one particular variation, the kitcomprises the compound in a multiple dose form.

In still another of its aspects, there is provided an article ofmanufacture comprising a compound of any one of the above embodimentsand variations; and packaging materials. In one variation, the packagingmaterial comprises a container for housing the compound. In oneparticular variation, the container comprises a label indicating one ormore members of the group consisting of a disease state for which thecompound is to be administered, storage information, dosing informationand/or instructions regarding how to administer the compound. In anothervariation, the article of manufacture comprises the compound in amultiple dose form.

In a further of its aspects, there is provided a therapeutic methodcomprising administering a compound of any one of the above embodimentsand variations to a subject.

In another of its aspects, there is provided a method of activatingglucokinase comprising contacting glucokinase with a compound of any oneof the above embodiments and variations.

In yet another of its aspects, there is provided a method of activatingglucokinase comprising causing a compound of any one of the aboveembodiments and variations to be present in a subject in order toactivate glucokinase in vivo.

In a further of its aspects, there is provided a method of activatingglucokinase comprising administering a first compound to a subject thatis converted in vivo to a second compound wherein the second compoundactivates glucokinase in vivo, the second compound being a compoundaccording to any one of the above embodiments and variations.

In another of its aspects, there is provided a method of treating adisease state for which increasing glucokinase activity ameliorates thepathology and/or symptomology of the disease state, the methodcomprising causing a compound of any one of the above embodiments andvariations to be present in a subject in a therapeutically effectiveamount for the disease state.

In yet another of its aspects, there is provided a method of treating adisease state for which increasing glucokinase activity ameliorates thepathology and/or symptomology of the disease state, the methodcomprising administering a compound of any one of the above embodimentsand variations to a subject, wherein the compound is present in thesubject in a therapeutically effective amount for the disease state.

In a further of its aspects, there is provided a method of treating adisease state for which increasing glucokinase activity ameliorates thepathology and/or symptomology of the disease state, the methodcomprising administering a first compound to a subject that is convertedin vivo to a second compound wherein the second compound activatesglucokinase in vivo, the second compound being a compound according toany one of the above embodiments and variations.

In one variation of each of the above methods the disease state ishyperglycemia. In another variation, the disease state is diabetes. Instill another variation, the disease state is dyslipidaemia. In yetanother variation, the disease state is obesity. In a further variation,the disease state is insulin resistance. In still a further variation,the disease state is metabolic syndrome X. In yet a further variation,the disease state is impaired glucose tolerance. In another variation,the disease state is polycystic ovary syndrome. In still anothervariation, the disease state is cardiovascular disease.

Salts, Hydrates, and Prodrugs of Glucokinase Activators

It should be recognized that the compounds of the present invention maybe present and optionally administered in the form of salts, hydratesand prodrugs that are converted in vivo into the compounds of thepresent invention. For example, it is within the scope of the presentinvention to convert the compounds of the present invention into and usethem in the form of their pharmaceutically acceptable salts derived fromvarious organic and inorganic acids and bases in accordance withprocedures well known in the art.

When the compounds of the present invention possess a free base form,the compounds can be prepared as a pharmaceutically acceptable acidaddition salt by reacting the free base form of the compound with apharmaceutically acceptable inorganic or organic acid, e.g.,hydrohalides such as hydrochloride, hydrobromide, hydroiodide; othermineral acids and their corresponding salts such as sulfate, nitrate,phosphate, etc.; and alkyl and monoarylsulfonates such asethanesulfonate, toluenesulfonate and benzenesulfonate; and otherorganic acids and their corresponding salts such as acetate, tartrate,maleate, succinate, citrate, benzoate, salicylate and ascorbate. Furtheracid addition salts of the present invention include, but are notlimited to: adipate, alginate, arginate, aspartate, bisulfate,bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate,chloride, chlorobenzoate, cyclopentanepropionate, digluconate,dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, fumarate,galacterate (from mucic acid), galacturonate, glucoheptaoate, gluconate,glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate,hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isethionate, iso-butyrate, lactate,lactobionate, malate, malonate, mandelate, metaphosphate,methanesulfonate, methylbenzoate, monohydrogenphosphate,2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate,pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate,phosphonate and phthalate. It should be recognized that the free baseforms will typically differ from their respective salt forms somewhat inphysical properties such as solubility in polar solvents, but otherwisethe salts are equivalent to their respective free base forms for thepurposes of the present invention.

When the compounds of the present invention possess a free acid form, apharmaceutically acceptable base addition salt can be prepared byreacting the free acid form of the compound with a pharmaceuticallyacceptable inorganic or organic base. Examples of such bases are alkalimetal hydroxides including potassium, sodium and lithium hydroxides;alkaline earth metal hydroxides such as barium and calcium hydroxides;alkali metal alkoxides, e.g., potassium ethanolate and sodiumpropanolate; and various organic bases such as ammonium hydroxide,piperidine, diethanolamine and N-methylglutamine. Also included are thealuminum salts of the compounds of the present invention. Further basesalts of the present invention include, but are not limited to: copper,ferric, ferrous, lithium, magnesium, manganic, manganous, potassium,sodium and zinc salts. Organic base salts include, but are not limitedto, salts of primary, secondary and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines andbasic ion exchange resins, e.g., arginine, betaine, caffeine,chloroprocaine, choline, N,N′-dibenzylethylenediamine(benzathine),dicyclohexylamine, diethanolamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, iso-propylamine, lidocaine, lysine, meglumine,N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamineresins, procaine, purines, theobromine, triethanolamine, triethylamine,trimethylamine, tripropylamine and tris-(hydroxymethyl)-methylamine(tromethamine). It should be recognized that the free acid forms willtypically differ from their respective salt forms somewhat in physicalproperties such as solubility in polar solvents, but otherwise the saltsare equivalent to their respective free acid forms for the purposes ofthe present invention.

Compounds of the present invention that comprise basicnitrogen-containing groups may be quaternized with such agents as (C₁₋₄)alkyl halides, e.g., methyl, ethyl, iso-propyl and tert-butyl chlorides,bromides and iodides; di(C₁₋₄) alkyl sulfates, e.g., dimethyl, diethyland diamyl sulfates; (C₁₀₋₁₈) alkyl halides, e.g., decyl, dodecyl,lauryl, myristyl and stearyl chlorides, bromides and iodides; andaryl(C₁₋₄) alkyl halides, e.g., benzyl chloride and phenethyl bromide.Such salts permit the preparation of both water-soluble and oil-solublecompounds of the present invention.

N-oxides of compounds according to the present invention can be preparedby methods known to those of ordinary skill in the art. For example,N-oxides can be prepared by treating an unoxidized form of the compoundwith an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid,perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, or thelike) in a suitable inert organic solvent (e.g., a halogenatedhydrocarbon such as dichloromethane) at approximately 0° C.Alternatively, the N-oxides of the compounds can be prepared from theN-oxide of an appropriate starting material.

Prodrug derivatives of compounds according to the present invention canbe prepared by modifying substituents of compounds of the presentinvention that are then converted in vivo to a different substituent. Itis noted that in many instances, the prodrugs themselves also fallwithin the scope of the range of compounds according to the presentinvention. For example, prodrugs can be prepared by reacting a compoundwith a carbamylating agent (e.g., 1,1-acyloxyalkylcarbonochloridate,para-nitrophenyl carbonate, or the like) or an acylating agent. Furtherexamples of methods of making prodrugs are described in Saulnier et al.(1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985.

Protected derivatives of compounds of the present invention can also bemade. Examples of techniques applicable to the creation of protectinggroups and their removal can be found in T. W. Greene, Protecting Groupsin Organic Synthesis, 3^(rd) edition, John Wiley & Sons, Inc. 1999.

Compounds of the present invention may also be conveniently prepared, orformed during the process of the invention, as solvates (e.g.,hydrates). Hydrates of compounds of the present invention may beconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents such as dioxin, tetrahydrofuranor methanol.

A “pharmaceutically acceptable salt”, as used herein, is intended toencompass any compound according to the present invention that isutilized in the form of a salt thereof, especially where the saltconfers on the compound improved pharmacokinetic properties as comparedto the free form of compound or a different salt form of the compound.The pharmaceutically acceptable salt form may also initially conferdesirable pharmacokinetic properties on the compound that it did notpreviously possess, and may even positively affect the pharmacodynamicsof the compound with respect to its therapeutic activity in the body. Anexample of a pharmacokinetic property that may be favorably affected isthe manner in which the compound is transported across cell membranes,which in turn may directly and positively affect the absorption,distribution, biotransformation and excretion of the compound. While theroute of administration of the pharmaceutical composition is important,and various anatomical, physiological and pathological factors cancritically affect bioavailability, the solubility of the compound isusually dependent upon the character of the particular salt formthereof, which it utilized. One of skill in the art will appreciate thatan aqueous solution of the compound will provide the most rapidabsorption of the compound into the body of a subject being treated,while lipid solutions and suspensions, as well as solid dosage forms,will result in less rapid absorption of the compound.

Compositions Comprising Glucokinase Activators

A wide variety of compositions and administration methods may be used inconjunction with the compounds of the present invention. Suchcompositions may include, in addition to the compounds of the presentinvention, conventional pharmaceutical excipients, and otherconventional, pharmaceutically inactive agents. Additionally, thecompositions may include active agents in addition to the compounds ofthe present invention. These additional active agents may includeadditional compounds according to the invention, and/or one or moreother pharmaceutically active agents.

The compositions may be in gaseous, liquid, semi-liquid or solid form,formulated in a manner suitable for the route of administration to beused. For oral administration, capsules and tablets are typically used.For parenteral administration, reconstitution of a lyophilized powder,prepared as described herein, is typically used.

Compositions comprising compounds of the present invention may beadministered or coadministered orally, parenterally, intraperitoneally,intravenously, intraarterially, transdermally, sublingually,intramuscularly, rectally, transbuccally, intranasally, liposomally, viainhalation, vaginally, intraoccularly, via local delivery (for exampleby catheter or stent), subcutaneously, intraadiposally,intraarticularly, or intrathecally. The compounds and/or compositionsaccording to the invention may also be administered or coadministered inslow release dosage forms.

The glucokinase activators and compositions comprising them may beadministered or coadministered in any conventional dosage form.Co-administration in the context of this invention is intended to meanthe administration of more than one therapeutic agent, one of whichincludes a glucokinase activator, in the course of a coordinatedtreatment to achieve an improved clinical outcome. Suchco-administration may also be coextensive, that is, occurring duringoverlapping periods of time.

Solutions or suspensions used for parenteral, intradermal, subcutaneous,or topical application may optionally include one or more of thefollowing components: a sterile diluent, such as water for injection,saline solution, fixed oil, polyethylene glycol, glycerine, propyleneglycol or other synthetic solvent; antimicrobial agents, such as benzylalcohol and methyl parabens; antioxidants, such as ascorbic acid andsodium bisulfite; chelating agents, such as ethylenediaminetetraaceticacid (EDTA); buffers, such as acetates, citrates and phosphates; agentsfor the adjustment of tonicity such as sodium chloride or dextrose, andagents for adjusting the acidity or alkalinity of the composition, suchas alkaline or acidifying agents or buffers like carbonates,bicarbonates, phosphates, hydrochloric acid, and organic acids likeacetic and citric acid. Parenteral preparations may optionally beenclosed in ampules, disposable syringes or single or multiple dosevials made of glass, plastic or other suitable material.

When compounds according to the present invention exhibit insufficientsolubility, methods for solubilizing the compounds may be used. Suchmethods are known to those of skill in this art, and include, but arenot limited to, using cosolvents, such as dimethylsulfoxide (DMSO),using surfactants, such as TWEEN, or dissolution in aqueous sodiumbicarbonate. Derivatives of the compounds, such as prodrugs of thecompounds may also be used in formulating effective pharmaceuticalcompositions.

Upon mixing or adding compounds according to the present invention to acomposition, a solution, suspension, emulsion or the like may be formed.The form of the resulting composition will depend upon a number offactors, including the intended mode of administration, and thesolubility of the compound in the selected carrier or vehicle. Theeffective concentration needed to ameliorate the disease being treatedmay be empirically determined.

Compositions according to the present invention are optionally providedfor administration to humans and animals in unit dosage forms, such astablets, capsules, pills, powders, dry powders for inhalers, granules,sterile parenteral solutions or suspensions, and oral solutions orsuspensions, and oil-water emulsions containing suitable quantities ofthe compounds, particularly the pharmaceutically acceptable salts,preferably the sodium salts, thereof. The pharmaceuticallytherapeutically active compounds and derivatives thereof are typicallyformulated and administered in unit-dosage forms or multiple-dosageforms. Unit-dose forms, as used herein, refers to physically discreteunits suitable for human and animal subjects and packaged individuallyas is known in the art. Each unit-dose contains a predetermined quantityof the therapeutically active compound sufficient to produce the desiredtherapeutic effect, in association with the required pharmaceuticalcarrier, vehicle or diluent. Examples of unit-dose forms includeampoules and syringes individually packaged tablet or capsule. Unit-doseforms may be administered in fractions or multiples thereof. Amultiple-dose form is a plurality of identical unit-dosage formspackaged in a single container to be administered in segregatedunit-dose form. Examples of multiple-dose forms include vials, bottlesof tablets or capsules or bottles of pint or gallons. Hence, multipledose form is a multiple of unit-doses that are not segregated inpackaging.

In addition to one or more compounds according to the present invention,the composition may comprise: a diluent such as lactose, sucrose,dicalcium phosphate, or carboxymethylcellulose; a lubricant, such asmagnesium stearate, calcium stearate and talc; and a binder such asstarch, natural gums, such as gum acaciagelatin, glucose, molasses,polyinylpyrrolidine, celluloses and derivatives thereof, povidone,crospovidones and other such binders known to those of skill in the art.Liquid pharmaceutically administrable compositions can, for example, beprepared by dissolving, dispersing, or otherwise mixing an activecompound as defined above and optional pharmaceutical adjuvants in acarrier, such as, for example, water, saline, aqueous dextrose,glycerol, glycols, ethanol, and the like, to form a solution orsuspension. If desired, the pharmaceutical composition to beadministered may also contain minor amounts of auxiliary substances suchas wetting agents, emulsifying agents, or solubilizing agents, pHbuffering agents and the like, for example, acetate, sodium citrate,cyclodextrine derivatives, sorbitan monolaurate, triethanolamine sodiumacetate, triethanolamine oleate, and other such agents. Actual methodsof preparing such dosage forms are known in the art, or will beapparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15thEdition, 1975. The composition or formulation to be administered will,in any event, contain a sufficient quantity of an activator of thepresent invention to increase glucokinase activity in vivo, therebytreating the disease state of the subject.

Dosage forms or compositions may optionally comprise one or morecompounds according to the present invention in the range of 0.005% to100% (weight/weight) with the balance comprising additional substancessuch as those described herein. For oral administration, apharmaceutically acceptable composition may optionally comprise any oneor more commonly employed excipients, such as, for examplepharmaceutical grades of mannitol, lactose, starch, magnesium stearate,talcum, cellulose derivatives, sodium crosscarmellose, glucose, sucrose,magnesium carbonate, sodium saccharin, talcum. Such compositions includesolutions, suspensions, tablets, capsules, powders, dry powders forinhalers and sustained release formulations, such as, but not limitedto, implants and microencapsulated delivery systems, and biodegradable,biocompatible polymers, such as collagen, ethylene vinyl acetate,polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid andothers. Methods for preparing these formulations are known to thoseskilled in the art. The compositions may optionally contain 0.01%-100%(weight/weight) of one or more glucokinase activators, optionally0.1-95%, and optionally 1-95%.

Salts, preferably sodium salts, of the activators may be prepared withcarriers that protect the compound against rapid elimination from thebody, such as time release formulations or coatings. The formulationsmay further include other active compounds to obtain desiredcombinations of properties.

Formulations for Oral Administration

Oral pharmaceutical dosage forms may be as a solid, gel or liquid.Examples of solid dosage forms include, but are not limited to tablets,capsules, granules, and bulk powders. More specific examples of oraltablets include compressed, chewable lozenges and tablets that may beenteric-coated, sugar-coated or film-coated. Examples of capsulesinclude hard or soft gelatin capsules. Granules and powders may beprovided in non-effervescent or effervescent forms. Each may be combinedwith other ingredients known to those skilled in the art.

In certain embodiments, compounds according to the present invention areprovided as solid dosage forms, preferably capsules or tablets. Thetablets, pills, capsules, troches and the like may optionally containone or more of the following ingredients, or compounds of a similarnature: a binder; a diluent; a disintegrating agent; a lubricant; aglidant; a sweetening agent; and a flavoring agent.

Examples of binders that may be used include, but are not limited to,microcrystalline cellulose, gum tragacanth, glucose solution, acaciamucilage, gelatin solution, sucrose and starch paste.

Examples of lubricants that may be used include, but are not limited to,talc, starch, magnesium or calcium stearate, lycopodium and stearicacid.

Examples of diluents that may be used include, but are not limited to,lactose, sucrose, starch, kaolin, salt, mannitol and dicalciumphosphate.

Examples of glidants that may be used include, but are not limited to,colloidal silicon dioxide.

Examples of disintegrating agents that may be used include, but are notlimited to, crosscarmellose sodium, sodium starch glycolate, alginicacid, corn starch, potato starch, bentonite, methylcellulose, agar andcarboxymethylcellulose.

Examples of coloring agents that may be used include, but are notlimited to, any of the approved certified water-soluble FD and C dyes,mixtures thereof, and water insoluble FD and C dyes suspended on aluminahydrate.

Examples of sweetening agents that may be used include, but are notlimited to, sucrose, lactose, mannitol and artificial sweetening agentssuch as sodium cyclamate and saccharin, and any number of spray-driedflavors.

Examples of flavoring agents that may be used include, but are notlimited to, natural flavors extracted from plants such as fruits andsynthetic blends of compounds that produce a pleasant sensation, suchas, but not limited to peppermint and methyl salicylate.

Examples of wetting agents that may be used include, but are not limitedto, propylene glycol monostearate, sorbitan monooleate, diethyleneglycol monolaurate and polyoxyethylene lauryl ether.

Examples of anti-emetic coatings that may be used include, but are notlimited to, fatty acids, fats, waxes, shellac, ammoniated shellac andcellulose acetate phthalates.

Examples of film coatings that may be used include, but are not limitedto, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethyleneglycol 4000 and cellulose acetate phthalate.

If oral administration is desired, the salt of the compound mayoptionally be provided in a composition that protects it from the acidicenvironment of the stomach. For example, the composition can beformulated in an enteric coating that maintains its integrity in thestomach and releases the active compound in the intestine. Thecomposition may also be formulated in combination with an antacid orother such ingredient.

When the dosage unit form is a capsule, it may optionally additionallycomprise a liquid carrier such as a fatty oil. In addition, dosage unitforms may optionally additionally comprise various other materials thatmodify the physical form of the dosage unit, for example, coatings ofsugar and other enteric agents.

Compounds according to the present invention may also be administered asa component of an elixir, suspension, syrup, wafer, sprinkle, chewinggum or the like. A syrup may optionally comprise, in addition to theactive compounds, sucrose as a sweetening agent and certainpreservatives, dyes and colorings and flavors.

The compounds of the present invention may also be mixed with otheractive materials that do not impair the desired action, or withmaterials that supplement the desired action, such as antacids, H2blockers, and diuretics. For example, if a compound is used for treatingasthma or hypertension, it may be used with other bronchodilators andantihypertensive agents, respectively.

Examples of pharmaceutically acceptable carriers that may be included intablets comprising compounds of the present invention include, but arenot limited to binders, lubricants, diluents, disintegrating agents,coloring agents, flavoring agents, and wetting agents. Enteric-coatedtablets, because of the enteric-coating, resist the action of stomachacid and dissolve or disintegrate in the neutral or alkaline intestines.Sugar-coated tablets may be compressed tablets to which different layersof pharmaceutically acceptable substances are applied. Film-coatedtablets may be compressed tablets that have been coated with polymers orother suitable coating. Multiple compressed tablets may be compressedtablets made by more than one compression cycle utilizing thepharmaceutically acceptable substances previously mentioned. Coloringagents may also be used in tablets. Flavoring and sweetening agents maybe used in tablets, and are especially useful in the formation ofchewable tablets and lozenges.

Examples of liquid oral dosage forms that may be used include, but arenot limited to, aqueous solutions, emulsions, suspensions, solutionsand/or suspensions reconstituted from non-effervescent granules andeffervescent preparations reconstituted from effervescent granules.

Examples of aqueous solutions that may be used include, but are notlimited to, elixirs and syrups. As used herein, elixirs refer to clear,sweetened, hydroalcoholic preparations. Examples of pharmaceuticallyacceptable carriers that may be used in elixirs include, but are notlimited to solvents. Particular examples of solvents that may be usedinclude glycerin, sorbitol, ethyl alcohol and syrup. As used herein,syrups refer to concentrated aqueous solutions of a sugar, for example,sucrose. Syrups may optionally further comprise a preservative.

Emulsions refer to two-phase systems in which one liquid is dispersed inthe form of small globules throughout another liquid. Emulsions mayoptionally be oil-in-water or water-in-oil emulsions. Examples ofpharmaceutically acceptable carriers that may be used in emulsionsinclude, but are not limited to non-aqueous liquids, emulsifying agentsand preservatives.

Examples of pharmaceutically acceptable substances that may be used innon-effervescent granules, to be reconstituted into a liquid oral dosageform, include diluents, sweeteners and wetting agents.

Examples of pharmaceutically acceptable substances that may be used ineffervescent granules, to be reconstituted into a liquid oral dosageform, include organic acids and a source of carbon dioxide.

Coloring and flavoring agents may optionally be used in all of the abovedosage forms.

Particular examples of preservatives that may be used include glycerin,methyl and propylparaben, benzoic add, sodium benzoate and alcohol.

Particular examples of non-aqueous liquids that may be used in emulsionsinclude mineral oil and cottonseed oil.

Particular examples of emulsifying agents that may be used includegelatin, acacia, tragacanth, bentonite, and surfactants such aspolyoxyethylene sorbitan monooleate.

Particular examples of suspending agents that may be used include sodiumcarboxymethylcellulose, pectin, tragacanth, Veegum and acacia. Diluentsinclude lactose and sucrose. Sweetening agents include sucrose, syrups,glycerin and artificial sweetening agents such as sodium cyclamate andsaccharin.

Particular examples of wetting agents that may be used include propyleneglycol monostearate, sorbitan monooleate, diethylene glycol monolaurateand polyoxyethylene lauryl ether.

Particular examples of organic acids that may be used include citric andtartaric acid.

Sources of carbon dioxide that may be used in effervescent compositionsinclude sodium bicarbonate and sodium carbonate. Coloring agents includeany of the approved certified water soluble FD and C dyes, and mixturesthereof.

Particular examples of flavoring agents that may be used include naturalflavors extracted from plants such fruits, and synthetic blends ofcompounds that produce a pleasant taste sensation.

For a solid dosage form, the solution or suspension, in for examplepropylene carbonate, vegetable oils or triglycerides, is preferablyencapsulated in a gelatin capsule. Such solutions, and the preparationand encapsulation thereof, are disclosed in U.S. Pat. Nos. 4,328,245;4,409,239; and 4,410,545. For a liquid dosage form, the solution, e.g.,for example, in a polyethylene glycol, may be diluted with a sufficientquantity of a pharmaceutically acceptable liquid carrier, e.g., water,to be easily measured for administration.

Alternatively, liquid or semi-solid oral formulations may be prepared bydissolving or dispersing the active compound or salt in vegetable oils,glycols, triglycerides, propylene glycol esters (e.g., propylenecarbonate) and other such carriers, and encapsulating these solutions orsuspensions in hard or soft gelatin capsule shells. Other usefulformulations include those set forth in U.S. Pat. Nos. Re 28,819 and4,358,603.

Injectables, Solutions, and Emulsions

The present invention is also directed to compositions designed toadminister the compounds of the present invention by parenteraladministration, generally characterized by subcutaneous, intramuscularor intravenous injection. Injectables may be prepared in anyconventional form, for example as liquid solutions or suspensions, solidforms suitable for solution or suspension in liquid prior to injection,or as emulsions.

Examples of excipients that may be used in conjunction with injectablesaccording to the present invention include, but are not limited towater, saline, dextrose, glycerol or ethanol. The injectablecompositions may also optionally comprise minor amounts of non-toxicauxiliary substances such as wetting or emulsifying agents, pH bufferingagents, stabilizers, solubility enhancers, and other such agents, suchas for example, sodium acetate, sorbitan monolaurate, triethanolamineoleate and cyclodextrins. Implantation of a slow-release orsustained-release system, such that a constant level of dosage ismaintained (see, e.g., U.S. Pat. No. 3,710,795) is also contemplatedherein. The percentage of active compound contained in such parenteralcompositions is highly dependent on the specific nature thereof, as wellas the activity of the compound and the needs of the subject.

Parenteral administration of the formulations includes intravenous,subcutaneous and intramuscular administrations. Preparations forparenteral administration include sterile solutions ready for injection,sterile dry soluble products, such as the lyophilized powders describedherein, ready to be combined with a solvent just prior to use, includinghypodermic tablets, sterile suspensions ready for injection, sterile dryinsoluble products ready to be combined with a vehicle just prior to useand sterile emulsions. The solutions may be either aqueous ornonaqueous.

When administered intravenously, examples of suitable carriers include,but are not limited to physiological saline or phosphate buffered saline(PBS), and solutions containing thickening and solubilizing agents, suchas glucose, polyethylene glycol, and polypropylene glycol and mixturesthereof.

Examples of pharmaceutically acceptable carriers that may optionally beused in parenteral preparations include, but are not limited to aqueousvehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents,buffers, antioxidants, local anesthetics, suspending and dispersingagents, emulsifying agents, sequestering or chelating agents and otherpharmaceutically acceptable substances.

Examples of aqueous vehicles that may optionally be used include SodiumChloride Injection, Ringers Injection, Isotonic Dextrose Injection,Sterile Water Injection, Dextrose and Lactated Ringers Injection.

Examples of nonaqueous parenteral vehicles that may optionally be usedinclude fixed oils of vegetable origin, cottonseed oil, corn oil, sesameoil and peanut oil.

Antimicrobial agents in bacteriostatic or fungistatic concentrations maybe added to parenteral preparations, particularly when the preparationsare packaged in multiple-dose containers and thus designed to be storedand multiple aliquots to be removed. Examples of antimicrobial agentsthat may be used include phenols or cresols, mercurials, benzyl alcohol,chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters,thimerosal, benzalkonium chloride and benzethonium chloride.

Examples of isotonic agents that may be used include sodium chloride anddextrose. Examples of buffers that may be used include phosphate andcitrate. Examples of antioxidants that may be used include sodiumbisulfate. Examples of local anesthetics that may be used includeprocaine hydrochloride. Examples of suspending and dispersing agentsthat may be used include sodium carboxymethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. Examples of emulsifying agentsthat may be used include Polysorbate 80 (TWEEN 80). A sequestering orchelating agent of metal ions include EDTA.

Pharmaceutical carriers may also optionally include ethyl alcohol,polyethylene glycol and propylene glycol for water miscible vehicles andsodium hydroxide, hydrochloric acid, citric acid or lactic acid for pHadjustment.

The concentration of an activator in the parenteral formulation may beadjusted so that an injection administers a pharmaceutically effectiveamount sufficient to produce the desired pharmacological effect. Theexact concentration of an activator and/or dosage to be used willultimately depend on the age, weight and condition of the patient oranimal as is known in the art.

Unit-dose parenteral preparations may be packaged in an ampoule, a vialor a syringe with a needle. All preparations for parenteraladministration should be sterile, as is know and practiced in the art.

Injectables may be designed for local and systemic administration.Typically a therapeutically effective dosage is formulated to contain aconcentration of at least about 0.1% w/w up to about 90% w/w or more,preferably more than 1% w/w of the glucokinase activator to the treatedtissue(s). The activator may be administered at once, or may be dividedinto a number of smaller doses to be administered at intervals of time.It is understood that the precise dosage and duration of treatment willbe a function of the location of where the composition is parenterallyadministered, the carrier and other variables that may be determinedempirically using known testing protocols or by extrapolation from invivo or in vitro test data. It is to be noted that concentrations anddosage values may also vary with the age of the individual treated. Itis to be further understood that for any particular subject, specificdosage regimens may need to be adjusted over time according to theindividual need and the professional judgment of the personadministering or supervising the administration of the formulations.Hence, the concentration ranges set forth herein are intended to beexemplary and are not intended to limit the scope or practice of theclaimed formulations.

The glucokinase activator may optionally be suspended in micronized orother suitable form or may be derivatized to produce a more solubleactive product or to produce a prodrug. The form of the resultingmixture depends upon a number of factors, including the intended mode ofadministration and the solubility of the compound in the selectedcarrier or vehicle. The effective concentration is sufficient forameliorating the symptoms of the disease state and may be empiricallydetermined.

Lyophilized Powders

The compounds of the present invention may also be prepared aslyophilized powders, which can be reconstituted for administration assolutions, emulsions and other mixtures. The lyophilized powders mayalso be formulated as solids or gels.

Sterile, lyophilized powder may be prepared by dissolving the compoundin a sodium phosphate buffer solution containing dextrose or othersuitable excipient. Subsequent sterile filtration of the solutionfollowed by lyophilization under standard conditions known to those ofskill in the art provides the desired formulation. Briefly, thelyophilized powder may optionally be prepared by dissolving dextrose,sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose orother suitable agent, about 1-20%, preferably about 5 to 15%, in asuitable buffer, such as citrate, sodium or potassium phosphate or othersuch buffer known to those of skill in the art at, typically, aboutneutral pH. Then, a glucokinase activator is added to the resultingmixture, preferably above room temperature, more preferably at about30-35° C., and stirred until it dissolves. The resulting mixture isdiluted by adding more buffer to a desired concentration. The resultingmixture is sterile filtered or treated to remove particulates and toinsure sterility, and apportioned into vials for lyophilization. Eachvial may contain a single dosage or multiple dosages of the activator.

Topical Administration

The compounds of the present invention may also be administered astopical mixtures. Topical mixtures may be used for local and systemicadministration. The resulting mixture may be a solution, suspension,emulsions or the like and are formulated as creams, gels, ointments,emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes,foams, aerosols, irrigations, sprays, suppositories, bandages, dermalpatches or any other formulations suitable for topical administration.

The glucokinase activators may be formulated as aerosols for topicalapplication, such as by inhalation (see, U.S. Pat. Nos. 4,044,126,4,414,209, and 4,364,923, which describe aerosols for delivery of asteroid useful for treatment of inflammatory diseases, particularlyasthma). These formulations for administration to the respiratory tractcan be in the form of an aerosol or solution for a nebulizer, or as amicrofine powder for insufflation, alone or in combination with an inertcarrier such as lactose. In such a case, the particles of theformulation will typically have diameters of less than 50 microns,preferably less than 10 microns.

The activators may also be formulated for local or topical application,such as for topical application to the skin and mucous membranes, suchas in the eye, in the form of gels, creams, and lotions and forapplication to the eye or for intracisternal or intraspinal application.Topical administration is contemplated for transdermal delivery and alsofor administration to the eyes or mucosa, or for inhalation therapies.Nasal solutions of the glucokinase activator alone or in combinationwith other pharmaceutically acceptable excipients can also beadministered.

Formulations for Other Routes of Administrations

Depending upon the disease state being treated, other routes ofadministration, such as topical application, transdermal patches, andrectal administration, may also be used. For example, pharmaceuticaldosage forms for rectal administration are rectal suppositories,capsules and tablets for systemic effect. Rectal suppositories are usedherein mean solid bodies for insertion into the rectum that melt orsoften at body temperature releasing one or more pharmacologically ortherapeutically active ingredients. Pharmaceutically acceptablesubstances utilized in rectal suppositories are bases or vehicles andagents to raise the melting point. Examples of bases include cocoabutter (theobroma oil), glycerin-gelatin, carbowax, (polyoxyethyleneglycol) and appropriate mixtures of mono-, di- and triglycerides offatty acids. Combinations of the various bases may be used. Agents toraise the melting point of suppositories include spermaceti and wax.Rectal suppositories may be prepared either by the compressed method orby molding. The typical weight of a rectal suppository is about 2 to 3gm. Tablets and capsules for rectal administration may be manufacturedusing the same pharmaceutically acceptable substance and by the samemethods as for formulations for oral administration.

Examples of Formulations

The following are particular examples of oral, intravenous and tabletformulations that may optionally be used with compounds of the presentinvention. It is noted that these formulations may be varied dependingon the particular compound being used and the indication for which theformulation is going to be used.

ORAL FORMULATION Compound of the Present Invention 10-100 mg Citric AcidMonohydrate 105 mg Sodium Hydroxide 18 mg Flavoring Water q.s. to 100 mL

INTRAVENOUS FORMULATION Compound of the Present Invention 0.1-10 mgDextrose Monohydrate q.s. to make isotonic Citric Acid Monohydrate 1.05mg Sodium Hydroxide 0.18 mg Water for Injection q.s. to 1.0 mL

TABLET FORMULATION Compound of the Present Invention  1%Microcrystalline Cellulose 73% Stearic Acid 25% Colloidal Silica  1%.Kits Comprising Glucokinase Activators

The invention is also directed to kits and other articles of manufacturefor treating diseases associated with glucokinase. It is noted thatdiseases are intended to cover all conditions for which increasingglucokinase activity (e.g., upregulation of glucokinase) ameliorates thepathology and/or symptomology of the condition.

In one embodiment, a kit is provided that comprises a compositioncomprising at least one activator of the present invention incombination with instructions. The instructions may indicate the diseasestate for which the composition is to be administered, storageinformation, dosing information and/or instructions regarding how toadminister the composition. The kit may also comprise packagingmaterials. The packaging material may comprise a container for housingthe composition. The kit may also optionally comprise additionalcomponents, such as syringes for administration of the composition. Thekit may comprise the composition in single or multiple dose forms.

In another embodiment, an article of manufacture is provided thatcomprises a composition comprising at least one activator of the presentinvention in combination with packaging materials. The packagingmaterial may comprise a container for housing the composition. Thecontainer may optionally comprise a label indicating the disease statefor which the composition is to be administered, storage information,dosing information and/or instructions regarding how to administer thecomposition. The kit may also optionally comprise additional components,such as syringes for administration of the composition. The kit maycomprise the composition in single or multiple dose forms.

It is noted that the packaging material used in kits and articles ofmanufacture according to the present invention may form a plurality ofdivided containers such as a divided bottle or a divided foil packet.The container can be in any conventional shape or form as known in theart which is made of a pharmaceutically acceptable material, for examplea paper or cardboard box, a glass or plastic bottle or jar, are-sealable bag (for example, to hold a “refill” of tablets forplacement into a different container), or a blister pack with individualdoses for pressing out of the pack according to a therapeutic schedule.The container that is employed will depend on the exact dosage forminvolved, for example a conventional cardboard box would not generallybe used to hold a liquid suspension. It is feasible that more than onecontainer can be used together in a single package to market a singledosage form. For example, tablets may be contained in a bottle that isin turn contained within a box. Typically the kit includes directionsfor the administration of the separate components. The kit form isparticularly advantageous when the separate components are preferablyadministered in different dosage forms (e.g., oral, topical, transdermaland parenteral), are administered at different dosage intervals, or whentitration of the individual components of the combination is desired bythe prescribing physician.

One particular example of a kit according to the present invention is aso-called blister pack. Blister packs are well known in the packagingindustry and are being widely used for the packaging of pharmaceuticalunit dosage forms (tablets, capsules, and the like). Blister packsgenerally consist of a sheet of relatively stiff material covered with afoil of a preferably transparent plastic material. During the packagingprocess recesses are formed in the plastic foil. The recesses have thesize and shape of individual tablets or capsules to be packed or mayhave the size and shape to accommodate multiple tablets and/or capsulesto be packed. Next, the tablets or capsules are placed in the recessesaccordingly and the sheet of relatively stiff material is sealed againstthe plastic foil at the face of the foil which is opposite from thedirection in which the recesses were formed. As a result, the tablets orcapsules are individually sealed or collectively sealed, as desired, inthe recesses between the plastic foil and the sheet. Preferably thestrength of the sheet is such that the tablets or capsules can beremoved from the blister pack by manually applying pressure on therecesses whereby an opening is formed in the sheet at the place of therecess. The tablet or capsule can then be removed via said opening.

Another specific embodiment of a kit is a dispenser designed to dispensethe daily doses one at a time in the order of their intended use.Preferably, the dispenser is equipped with a memory-aid, so as tofurther facilitate compliance with the regimen. An example of such amemory-aid is a mechanical counter that indicates the number of dailydoses that has been dispensed. Another example of such a memory-aid is abattery-powered micro-chip memory coupled with a liquid crystal readout,or audible reminder signal which, for example, reads out the date thatthe last daily dose has been taken and/or reminds one when the next doseis to be taken.

Dosage, Host and Safety

The compounds of the present invention are stable and can be usedsafely. In particular, the compounds of the present invention are usefulas glucokinase activators for a variety of subjects (e.g., humans,non-human mammals and non-mammals). The optimal dose may vary dependingupon such conditions as, for example, the type of subject, the bodyweight of the subject, the route of administration, and specificproperties of the particular compound being used. In general, the dailydose for oral administration to an adult (body weight of about 60 kg) isabout 1 to 1000 mg, about 3 to 300 mg, or about 10 to 200 mg. It will beappreciated that the daily dose can be given in a single administrationor in multiple (e.g., 2 or 3) portions a day.

Combination Therapy

A wide variety of therapeutic agents may have a therapeutic additive orsynergistic effect with GK activators according to the presentinvention. In particular, the present invention also relates to the useof the GK activators of the present invention in combination with one ormore other antidiabetic compounds. Examples of such other antidiabeticcompounds include, but are not limited to S9 proteases, like dipeptidylpeptidase IV (DPP-IV) inhibitors; insulin signaling pathway modulators,like protein tyrosine phosphatase (PTPase) inhibitors, andglutamine-fructose-6-phosphate amidotransferase (GFAT) inhibitors;compounds influencing a dysregulated hepatic glucose production, likeglucose-6-phosphatase (G6Pase) inhibitors, fructose-1,6-bisphosphatase(F-1,6-BPase) inhibitors, glycogen phosphorylase (GP) inhibitors,glucagon receptor antagonists and phosphoenolpyruvate carboxykinase(PEPCK) inhibitors; pyruvate dehydrogenase kinase (PDHK) inhibitors;insulin sensitivity enhancers (insulin sensitizers); insulin secretionenhancers (insulin secretagogues); alpha-glucosidase inhibitors;inhibitors of gastric emptying; other glucokinase (GK) activators; GLP-1receptor agonists; UCP modulators; RXR modulators; GSK-3 inhibitors;PPAR modulators; metformin; insulin; and α₂-adrenergic antagonists. Thecompound of the present invention may be administered with such at leastone other antidiabetic compound either simultaneously as a single dose,at the same time as separate doses, or sequentially (i.e., where one isadministered before or after the other is administered).

In the case of combination therapy with compounds of the presentinvention, the other antidiabetic compound may be administered (e.g.,route and dosage form) in a manner known per se for such compound.Compounds of the present invention and the other antidiabetic compoundmay be administered sequentially (i.e., at separate times) or at thesame time, either one after the other separately in two separate doseforms or in one combined, single dose form. In one particularembodiment, the other antidiabetic compound is administered withcompounds of the present invention as a single, combined dosage form.The dose of the antidiabetic compound may be selected from the rangeknown to be clinically employed for such compound. Any of thetherapeutic compounds of diabetic complications, antihyperlipemiccompounds or antiobestic compounds can be used in combination withcompounds of the present invention in the same manner as the aboveantidiabetic compounds.

EXAMPLES Preparation of Glucokinase Activators

Various methods may be developed for synthesizing compounds according tothe present invention. Representative methods for synthesizing thesecompounds are provided in the Examples. It is noted, however, that thecompounds of the present invention may also be synthesized by othersynthetic routes that others may devise.

It will be readily recognized that certain compounds according to thepresent invention have atoms with linkages to other atoms that confer aparticular stereochemistry to the compound (e.g., chiral centers). It isrecognized that synthesis of compounds according to the presentinvention may result in the creation of mixtures of differentstereoisomers (i.e., enantiomers and diastereomers). Unless a particularstereochemistry is specified, recitation of a compound is intended toencompass all of the different possible stereoisomers.

Various methods for separating mixtures of different stereoisomers areknown in the art. For example, a racemic mixture of a compound may bereacted with an optically active resolving agent to form a pair ofdiastereoisomeric compounds. The diastereomers may then be separated inorder to recover the optically pure enantiomers. Dissociable complexesmay also be used to resolve enantiomers (e.g., crystallinediastereoisomeric salts). Diastereomers typically have sufficientlydistinct physical properties (e.g., melting points, boiling points,solubilities, reactivity, etc.) and can be readily separated by takingadvantage of these dissimilarities. For example, diastereomers cantypically be separated by chromatography or by separation/resolutiontechniques based upon differences in solubility. A more detaileddescription of techniques that can be used to resolve stereoisomers ofcompounds from their racemic mixture can be found in Jean Jacques AndreCollet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, JohnWiley & Sons, Inc. (1981).

Compounds according to the present invention can also be prepared as apharmaceutically acceptable acid addition salt by reacting the free baseform of the compound with a pharmaceutically acceptable inorganic ororganic acid. Alternatively, a pharmaceutically acceptable base additionsalt of a compound can be prepared by reacting the free acid form of thecompound with a pharmaceutically acceptable inorganic or organic base.Inorganic and organic acids and bases suitable for the preparation ofthe pharmaceutically acceptable salts of compounds are set forth in thedefinitions section of this Application. Alternatively, the salt formsof the compounds can be prepared using salts of the starting materialsor intermediates.

The free acid or free base forms of the compounds can be prepared fromthe corresponding base addition salt or acid addition salt form. Forexample, a compound in an acid addition salt form can be converted tothe corresponding free base by treating with a suitable base (e.g.,ammonium hydroxide solution, sodium hydroxide, and the like). A compoundin a base addition salt form can be converted to the corresponding freeacid by treating with a suitable acid (e.g., hydrochloric acid, etc).

The N-oxides of compounds according to the present invention can beprepared by methods known to those of ordinary skill in the art. Forexample, N-oxides can be prepared by treating an unoxidized form of thecompound with an oxidizing agent (e.g., trifluoroperacetic acid,permaleic acid, perbenzoic acid, peracetic acid,meta-chloroperoxybenzoic acid, or the like) in a suitable inert organicsolvent (e.g., a halogenated hydrocarbon such as dichloromethane) atapproximately 0° C. Alternatively, the N-oxides of the compounds can beprepared from the N-oxide of an appropriate starting material.

Compounds in an unoxidized form can be prepared from N-oxides ofcompounds by treating with a reducing agent (e.g., sulfur, sulfurdioxide, triphenyl phosphine, lithium borohydride, sodium borohydride,phosphorus trichloride, tribromide, or the like) in an suitable inertorganic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, or thelike) at 0 to 80° C.

Prodrug derivatives of the compounds can be prepared by methods known tothose of ordinary skill in the art (e.g., for further details seeSaulnier et al. (1994), Bioorganic and Medicinal Chemistry Letters, Vol.4, p. 1985). For example, appropriate prodrugs can be prepared byreacting a non-derivatized compound with a suitable carbamylating agent(e.g., 1,1-acyloxyalkylcarbonochloridate, para-nitrophenyl carbonate, orthe like).

Protected derivatives of the compounds can be made by methods known tothose of ordinary skill in the art. A detailed description of thetechniques applicable to the creation of protecting groups and theirremoval can be found in T. W. Greene, Protecting Groups in OrganicSynthesis, 3^(rd) edition, John Wiley & Sons, Inc. 1999.

Compounds according to the present invention may be convenientlyprepared, or formed during the process of the invention, as solvates(e.g., hydrates). Hydrates of compounds of the present invention may beconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents such as dioxin, tetrahydrofuranor methanol.

Compounds according to the present invention can also be prepared astheir individual stereoisomers by reacting a racemic mixture of thecompound with an optically active resolving agent to form a pair ofdiastereoisomeric compounds, separating the diastereomers and recoveringthe optically pure enantiomer. While resolution of enantiomers can becarried out using covalent diastereomeric derivatives of compounds,dissociable complexes are preferred (e.g., crystalline diastereoisomericsalts). Diastereomers have distinct physical properties (e.g., meltingpoints, boiling points, solubilities, reactivity, etc.) and can bereadily separated by taking advantage of these dissimilarities. Thediastereomers can be separated by chromatography or, preferably, byseparation/resolution techniques based upon differences in solubility.The optically pure enantiomer is then recovered, along with theresolving agent, by any practical means that would not result inracemization. A more detailed description of the techniques applicableto the resolution of stereoisomers of compounds from their racemicmixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen,Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).

As used herein the symbols and conventions used in these processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Standard single-letteror three-letter abbreviations are generally used to designate amino acidresidues, which are assumed to be in the L-configuration unlessotherwise noted. Unless otherwise noted, all starting materials wereobtained from commercial suppliers and used without furtherpurification. Specifically, the following abbreviations may be used inthe examples and throughout the specification:

μL (microliters) Ac (acetyl) atm (atmosphere) ATP (AdenosineTriphophatase) BOC BOP (bis(2-oxo-3- (tert-butyloxycarbonyl)oxazolidinyl)phosphinic chloride) BSA (Bovine Serum Albumin) CBZ(benzyloxycarbonyl) CDI (1,1-carbonyldiimidazole) DCC(dicyclohexylcarbodiimide) DCE (dichloroethane) DCM (dichloromethane)DMAP (4-dimethylaminopyridine) DME (1,2-dimethoxyethane) DMF DMPU (N,N'-(N,N-dimethylformamide) dimethylpropyleneurea) DMSO EDCI(ethylcarbodiimide (dimethylsulfoxide) hydrochloride) EDTA(Ethylenediaminetetraacetic Et (ethyl) acid) Et₂O (diethyl ether) EtOAc(ethyl acetate) FMOC (9-fluorenylmethoxycarbonyl) g (grams) h (hours)HOAc or AcOH (acetic acid) HOBT (1-hydroxybenzotriazole) HOSu(N-hydroxysuccinimide) HPLC (high pressure liquid Hz (Hertz)chromatography) i.v. (intravenous) IBCF (isobutyl chloroformate) i-PrOH(isopropanol) L (liters) M (molar) mCPBA (meta-chloroperbenzoic acid) Me(methyl) MeOH (methanol) mg (milligrams) MHz (megahertz) min (minutes)mL (milliliters) mM (millimolar) mmol (millimoles) mol (moles) MOPS(Morpholinepropanesulfonic acid) mp (melting point) NaOAc (sodiumacetate) OMe (methoxy) psi (pounds per square inch) RP (reverse phase)RT (ambient temperature) SPA (Scintillation TBAF (tetra-n-butylammoniumProximity Assay) fluoride) TBS (t-butyldimethylsilyl) tBu (tert-butyl)TEA (triethylamine) TFA (trifluoroacetic acid) TFAA (trifluoroaceticanhydride) THF (tetrahydrofuran) TIPS (triisopropylsilyl) TLC (thinlayer chromatography) TMS (trimethylsilyl) TMSE(2-(trimethylsilyl)ethyl) Tr (retention time)

All references to ether or Et₂O are to diethyl ether; and brine refersto a saturated aqueous solution of NaCl. Unless otherwise indicated, alltemperatures are expressed in ° C. (degrees Centigrade). All reactionsare conducted under an inert atmosphere at RT unless otherwise noted.

¹H NMR spectra were recorded on a Bruker Avance 400. Chemical shifts areexpressed in parts per million (ppm). Coupling constants are in units ofHertz (Hz). Splitting patterns describe apparent multiplicities and aredesignated as s (singlet), d (doublet), t (triplet), q (quartet), m(multiplet), br (broad).

Low-resolution mass spectra (MS) and compound purity data were acquiredon a Waters ZQ LC/MS single quadrupole system equipped with electrosprayionization (ESI) source, UV detector (220 and 254 nm), and evaporativelight scattering detector (ELSD). Thin-layer chromatography wasperformed on 0.25 mm E. Merck silica gel plates (60F-254), visualizedwith UV light, 5% ethanolic phosphomolybdic acid, Ninhydrin orp-anisaldehyde solution. Flash column chromatography was performed onsilica gel (230-400 mesh, Merck).

The starting materials and reagents used in preparing these compoundsare either available from commercial suppliers such as the AldrichChemical Company (Milwaukee, Wis.), Bachem (Torrance, Calif.), Sigma(St. Louis, Mo.), or may be prepared by methods well known to a personof ordinary skill in the art, following procedures described in suchstandard references as Fieser and Fieser's Reagents for OrganicSynthesis, vols. 1-17, John Wiley and Sons, New York, N.Y., 1991; Rodd'sChemistry of Carbon Compounds, vols. 1-5 and supps., Elsevier SciencePublishers, 1989; Organic Reactions, vols. 1-40, John Wiley and Sons,New York, N.Y., 1991; March J.: Advanced Organic Chemistry, 4th ed.,John Wiley and Sons, New York, N.Y.; and Larock: Comprehensive OrganicTransformations, VCH Publishers, New York, 1989.

The entire disclosures of all documents cited throughout thisapplication are incorporated herein by reference.

Synthetic Schemes for Compounds of the Present Invention

Compounds according to the present invention may be synthesizedaccording to the reaction schemes shown below. Other reaction schemescould be readily devised by those skilled in the art. It should also beappreciated that a variety of different solvents, temperatures and otherreaction conditions can be varied to optimize the yields of thereactions.

In the reactions described hereinafter it may be necessary to protectreactive functional groups, for example hydroxy, amino, imino, thio orcarboxy groups, where these are desired in the final product, to avoidtheir unwanted participation in the reactions. Conventional protectinggroups may be used in accordance with standard practice, for examplessee T. W. Greene and P. G. M. Wuts in “Protective Groups in OrganicChemistry” John Wiley and Sons, 1991.

Referring to Scheme 1a, Compound A is reacted with Compound B underheating to give Compound C. In one embodiment, LG₁ is halo (e.g., Br).In another embodiment, LG₂ is OH or a (C₁₋₃)alkoxy. In particular, whenQ is SO₂, LG₂ is preferably a (C₁₋₃)alkoxy. After coupling with amine,Compound D is obtained.

Referring to Scheme 1b, Compound A is reacted with Compound B underheating to give Compound C. In one embodiment, LG₁ is halo (e.g., Br).In another embodiment, LG₂ is OH or a (C₁₋₃)alkoxy. In particular, whenQ is SO₂, LG₂ is preferably a (C₁₋₃)alkoxy. After coupling with amine,Compound D is obtained.

Referring to Scheme 2a, Compound F can be made from protected acidCompound E followed by deprotection. In one embodiment, LG₂ is OH or a(C₁₋₃)alkoxy. In particular, when Q is SO₂, LG₂ is preferably a(C₁₋₃)alkoxy. In another embodiment, LG₃ is halo (e.g., Br). Compound Freacts with Compound G to give Compound H.

Referring to Scheme 2b, Compound F can be made from protected acidCompound E followed by deprotection. In one embodiment, LG₂ is OH or a(C₁₋₃)alkoxy. In particular, when Q is SO₂, LG₂ is preferably a(C₁₋₃)alkoxy. In another embodiment, LG₃ is halo (e.g., Br). Compound Freacts with Compound G to give Compound H.

Referring to Scheme 3a, Compound I reacted with Compound B under heatingto give Compound J. In one embodiment, LG₂ is OH or a (C₁₋₃)alkoxy. Inparticular, when Q is SO₂, LG₂ is preferably a (C₁₋₃)alkoxy. Aftercoupling with amine, Compound K was obtained.

Referring to Scheme 3b, Compound I reacted with Compound B under heatingto give Compound J. In one embodiment, LG₂ is OH or a (C₁₋₃)alkoxy. Inparticular, when Q is SO₂, LG₂ is preferably a (C₁₋₃)alkoxy. Aftercoupling with amine, Compound K was obtained.

Chiral components can be separated and purified using any of a varietyof techniques known to those skilled in the art. For example, chiralcomponents can be purified using supercritical fluid chromatography(SFC). In one particular variation, chiral analytical SFC/MS analysesare conducted using a Berger analytical SFC system (AutoChem, Newark,Del.) which consists of a Berger SFC dual pump fluid control module witha Berger FCM 1100/1200 supercritical fluid pump and FCM 1200 modifierfluid pump, a Berger TCM 2000 oven, and an Alcott 718 autosampler. Theintegrated system can be controlled by BI-SFC Chemstation softwareversion 3.4. Detection can be accomplished with a Watrers ZQ 2000detector operated in positive mode with an ESI interface and a scanrange from 200-800 Da with 0.5 second per scan. Chromatographicseparations can be performed on a ChiralPak AD-H, ChiralPak AS-H,ChiralCel OD-H, or ChiralCel OJ-H column (5μ, 4.6×250 mm; ChiralTechnologies, Inc. West Chester, Pa.) with 10 to 40% methanol as themodifier and with or without ammonium acetate (10 mM). Any of a varietyof flow rates can be utilized including, for example, 1.5 or 3.5 mL/minwith an inlet pressure set at 100 bar. Additionally, a variety of sampleinjection conditions can be used including, for example, sampleinjections of either 5 or 10 μL in methanol at 0.1 mg/mL inconcentration.

In another variation, preparative chiral separations are performed usinga Berger MultiGram II SFC purification system. For example, samples canbe loaded onto a ChiralPak AD column (21×250 mm, 10μ). In particularvariations, the flow rate for separation can be 70 mL/min, the injectionvolume up to 2 mL, and the inlet pressure set at 130 bar. Stackedinjections can be applied to increase the efficiency.

In each of the above reaction procedures or schemes, the varioussubstituents may be selected from among the various substituentsotherwise taught herein.

Descriptions of the syntheses of particular compounds according to thepresent invention based on the above reaction scheme are set forthherein.

Examples of Glucokinase Activators

The present invention is further exemplified, but not limited by, thefollowing examples that describe the synthesis of particular compoundsaccording to the invention.

Compound 1: 2-(2H-indazol-2-yl)-4-methylpentanoic acid

Referring to Scheme 1, a mixture of indazole (450 mg, 3.86 mmol) and2-bromo-4-methylpentanoic acid (1.5 eq.) was heated to 160° C. for 4hours. The mixture was cooled, diluted with water, extracted by EtOAc,and dried over MgSO₄. The solvent was then removed to give the crudeproduct, which was used for the next step without further purification.[M+H] calc'd for C₁₄H₁₆N₂O₄, 233. found, 233.

Compound 2: 2-(2H-indazol-2-yl)-4-methyl-N-(thiazol-2-yl)pentanamide

A mixture of Compound 1 (640 mg, 2.76 mmol), 2-aminothiazole (284 mg,2.76 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HBTU) (1.0 g, 2.76 mmol) and 0.2 mL of Et₃N in DMF(4 mL) was stirred at room temperature for 2 hours to provide the titlecompound, which was then purified by HPLC. ¹H NMR (400 MHz, DMSO-d6) δ:7.74 (d, J=12.0 Hz, 1H), 7.60 (d, J=12.0 Hz, 1H), 7.51 (d, J=4.0 Hz,1H), 7.25 (m, 2H), 7.05 (t, J=8.0, 8.0 Hz, 1H), 5.67 (m, 1H), 2.23 (m,1H), 2.06 (m, 1H), 1.32 (m, 1H), 0.94 (d, J=8.0 Hz, 3H), 0.90 (d, J=8.0Hz, 3H). [M+H] calc'd for C₁₆H₁₈OS, 314. found, 314.

Compound 3:2-(5-fluoro-2H-indazol-2-yl)-4-methyl-N-(thiazol-2-yl)pentanamide

The title compound was synthesized according to the method described inconnection with Compound 2. ¹H NMR (400 MHz, MeOH-d4) δ: 7.66 (m, 1H),7.46 (d, J=4.0 Hz, 1H), 7.36 (dd, J=8.0, 4.0 Hz, 1H), 7.15 (m, 2H), 5.60(m, 1H), 2.38 (m, 1H), 2.12 (m, 1H), 1.37 (m, 1H), 1.02 (d, J=4.0 Hz,3H), 0.94 (d, J=8.0 Hz, 3H). [M+H] calc'd for C₁₆H₁₇FN₄OS, 332. found,332.

Compound 4:4-methyl-2-(6-nitro-2H-indazol-2-yl)-N-(thiazol-2-yl)pentanamide

The title compound was synthesized according to the method described inconnection with Compound 2. ¹H NMR (400 MHz, MeOH-d4) δ: 8.67 (s, 1H),8.62 (s, 1H), 7.93 (d, J=12.0 Hz, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.45 (d,J=4.0 Hz, 1H), 7.14 (d, J=4.0 Hz, 1H), 5.71 (m, 1H), 2.41 (m, 1H), 2.16(m, 1H), 1.37 (m, 1H), 1.02 (d, 4.0 Hz, 3H), 0.95 (d, 4.0 Hz, 3H). [M+H]calc'd for C₁₆H₁₇N₅O₃S, 359. found, 359.

Compound 5:4-methyl-2-(6-(methylsulfonyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)pentanamide

The title compound was synthesized according to the method described inconnection with Compound 2. ¹H NMR (400 MHz, MeOH-d4) δ: 8.68 (s, 1H),8.33 (s, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.46 (d,J=2.0 Hz, 1H), 7.17 (d, J=4.0 Hz, 1H), 5.72 (m, 1H), 3.16 (s, 3H), 2.42(m, 1H), 2.17 (m, 1H), 1.37 (m, 1H), 1.02 (d, J=8.0 Hz, 3H), 0.95 (d,J=8.0 Hz, 3H). [M+H] calc'd for C₁₇H₂₀N₄O₃S, 392. found, 392.

Compound 6:2-(5-methoxy-2H-indazol-2-yl)-4-methyl-N-(thiazol-2-yl)pentanamide

The title compound was synthesized according to the method described inconnection with Compound 2. ¹H NMR (400 MHz, MeOH-d4) δ: 8.33 (s, 1H),7.53 (d, J=12.0 Hz, 1H), 7.47 (d, J=4.0 Hz, 1H), 7.18 (d, J=4.0 Hz, 1H),7.03 (m, 2H), 5.55 (m, 1H), 3.82 (s, 3H), 2.37 (m, 1H), 2.10 (m, 1H),1.36 (m, 1H), 1.02 (d, J=4.0 Hz, 3H), 0.94 (d, J=8.0 Hz, 3H). [M+H]calc'd for C₁₇H₂₀N₄O₂S, 344. found, 344.

Compound 7:2-(5-hydroxy-2H-indazol-2-yl)-4-methyl-N-(thiazol-2-yl)pentanamide

The title compound was synthesized according to the method described inconnection with Compound 2. ¹H NMR (400 MHz, MeOH-d4) δ: 8.21 (s, 1H),7.50 (d, J=8.0 Hz, 1H), 7.44 (d, J=4.0 Hz, 1H), 7.15 (d, J=4.0 Hz, 1H),6.99 (m, 1H), 6.92 (d, J=2.0 Hz, 1H), 5.51 (m, 1H), 2.36 (m, 1H), 2.09(m, 1H), 1.37 (m, 1H), 1.01 (d, J=8.0 Hz, 3H), 0.94 (d, J=4.0 Hz, 3H).[M+H] calc'd for C₁₆H₁₈N₄O₂S, 330. found, 330.

Compound 8:4-methyl-2-(3-methyl-2H-indazol-2-yl)-N-(thiazol-2-yl)pentanamide

The title compound was synthesized according to the method described inconnection with Compound 2. ¹H NMR (400 MHz, MeOH-d4) δ: 7.74 (d, J=8.0Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.41 (m, 2H), 7.14 (m, 2H), 5.62 (m,1H), 2.77 (s, 3H), 2.46 (m, 1H), 2.21 (m, 1H), 1.37 (m, 1H), 1.00 (d,J=8.0 Hz, 3H), 0.93 (d, J=4.0 Hz, 3H). [M+H] calc'd for C₁₇H₂₀N₄OS, 328.found, 328.

Compound 9:2-(5-fluoro-3-methyl-2H-indazol-2-yl)-4-methyl-N-(thiazol-2-yl)pentanamide

The title compound was synthesized according to the method described inconnection with Compound 2. ¹H NMR (400 MHz, MeOH-d4) δ: 7.62 (m, 1H),7.42 (d, J=2.0 Hz, 1H), 7.30 (dd, J=4.0, 8.0 Hz, 1H), 7.14 (m, 2H), 5.55(m, 1H), 2.68 (s, 3H), 2.45 (m, 1H), 2.17 (m, 1H), 0.99 (d, J=4.0 Hz,3H), 0.92 (d, J=4.0 Hz, 3H). [M+H] calc'd for C₁₇H₁₉FNOS, 346. found,346.

Compound 10: 2-amino-3-cyclohexyl-N-(thiazol-2-yl)propanamide, HCl salt

Referring to Scheme 2, a mixture of2-(tert-butoxycarbonylamino)-3-cyclohexylpropanoic acid (0.5 g, 1.85mmol), 2-aminothiazole (0.19 g, 1.85 mmol) and HBTU (0.72 g, 1.9 mmol)was stirred at room temperature for 2 hours. The mixture was dilutedwith water, extracted by EtOAc and dried over MgSO₄. The solvent wasremoved and the product dissolved in 5 mL dioxane. 2 mL of 4 M HCl indioxane was added, the mixture was stirred overnight, and the solventremoved to give the title compound as an HCl salt. [M+H] calc'd forC₁₂H₁₉N₃OS, 254. found, 254.

Compound 11:3-cyclohexyl-2-(1-iminoisoindolin-2-yl)-N-(thiazol-2-yl)propanamide

The solution of Compound 10 (100 mg, 0.35 mmol), 2-cyanobenzyl bromide(67 mg, 0.35 mmol) and 0.2 mL of TEA in 5 mL of DCM was stirred at roomtemperature for 4 hrs. The solvent was removed and the product purifiedby HPLC to yield the title compound. ¹H NMR (400 MHz, MeOH-d4) δ: 8.14(d, J=8.0 Hz, 1H), 7.62-7.90 (m, 3H), 7.45 (d, J=4.0 Hz, 1H), 7.14 (d,J=4.0 Hz, 1H), 5.12-5.22 (m, 2H), 4.99 (d, J=20.0 Hz, 1H), 2.10-2.28 (m,2H), 1.62-1.92 (m, 5H), 1.08-139 (m, 6H). [M+H] calc'd for C₂₀H₂₄N₄OS,369. found, 369.

Compound 12:3-cyclohexyl-2-(6-fluoro-1-iminoisoindolin-2-yl)-N-(thiazol-2-yl)propanamide

The title compound was synthesized according to the method described inconnection with Compound 11, except that 2-cyano-4-fluoromethylbenzylbromide was used. ¹H NMR (400 MHz, MeOH-d4) δ: 7.99 (dd, J=2.4, 8.0 Hz,1H), 7.76-7.82 (m, 1H), 7.58-7.66 (m, 1H), 7.44 (d, J=0.6 Hz, 1H), 7.13(d, J=0.6 Hz, 1H), 5.11-5.21 (m, 2H), 4.96 (d, J=20.0 Hz, 1H), 2.03-2.24(m, 2H), 1.70-1.90 (m, 5H), 1.0-138 (m, 6H). [M+H] calc'd forC₂₀H₂₃FN₄OS, 387. found, 387.

Compound 13:2-(1,3-dioxoisoindolin-2-yl)-4-methyl-N-(thiazol-2-yl)pentanamide

Referring to Scheme 3, a mixture of2-(1,3-dioxoisoindolin-2-yl)-4-methylpentanoic acid (78 mg, 0.3 mmol),2-aminothiazole (30 mg, 0.3 mmol), HBTU (114 mg, 0.3 mmol) and 0.1 mL ofEt₃N in DMF (2 mL) was stirred at room temperature for 2 hours toprovide the title compound, which was then purified by HPLC. ¹H NMR (400MHz, MeOH-d4) δ: 7.83-7.86 (m, 2H), 7.89-7.92 (m, 2H), 7.41 (d, J=3.2Hz, 1H), 7.12 (d, J=3.2 Hz, 1H), 5.15 (dd, J=4.8, 11.6 Hz, 2H),2.35-2.45 (m, 1H), 1.96-2.05 (m, 1H), 1.51 (m, 1H), 0.99 (d, J=6.4 Hz,3H), 0.95 (d, J=6.4 Hz, 3H). [M+H] calc'd for C₁₇H₁₇N₃O₃S, 344. found,344.

Compound 14:2-(1,3-dioxoisoindolin-2-yl)-4-methyl-N-(pyridin-2-yl)pentanamide

The title compound was synthesized according to the method described inconnection with Compound 13, except that 2-aminopyridine was used. ¹HNMR (400 MHz, MeOH-d4) δ: 8.34 (dd, J=1.2, 6.0 Hz, 1H), 8.12-8.17 (m,1H), 7.91-7.94 (m, 2H), 7.85-7.88 (m, 2H), 7.79 (d, J=7.2 Hz, 1H),7.38-7.43 (m, 1H), 5.19 (dd, J=4.4, 11.2 Hz, 1H) 2.35-2.44 (m, 1H),1.97-2.06 (m, 1H), 1.51 (m, 1H) 1.0 (d, J=6.4 Hz, 3H), 0.97 (d, J=6.4Hz, 3H). [M+H] calc'd for C₁₉H₁₉N₃O₃, 338. found, 338.

In addition to the foregoing, the above reaction schemes and variationsthereof can be used to prepare the following:

Biological Testing

The activity of compounds as glucokinase activators may be assayed invitro, in vivo or in a cell line. Provided below is an enzymaticglucokinase activity assay.

Purified glucokinase may be obtained as follows. DNA encoding residues12-465 of the full-length sequence of the human enzyme may be amplifiedby PCR and cloned into the HindIII and EcoRI sites of pFLAG-CTC (Sigma).SEQ. I.D. No. 1 corresponds to residues 12-465 of glucokinase.

The expression of recombinant glucokinase protein may be carried out bytransformation and growth of DH10b-T1r E. coli cells incorporating the(pFLAG-CTC) plasmid in LB media. Protein expression can be induced inthis system by the addition of IPTG to the culture medium.

Recombinant protein may be isolated from cellular extracts by passageover Sepharose Q Fast Flow resin (Pharmacia). This partially purified GKextract may then be further purified by a second passage over Poros HQ10(Applied Biosystems). The purity of GK may be determined on denaturingSDS-PAGE gel. Purified GK may then be concentrated to a finalconcentration of 20.0 mg/ml. After flash freezing in liquid nitrogen,the proteins can be stored at −78° C. in a buffer containing 25 mMTRIS-HCl pH 7.6, 50 mM NaCl, and 0.5 mM TCEP.

It should be noted that a variety of other expression systems and hostsare also suitable for the expression of glucokinase, as would be readilyappreciated by one of skill in the art.

The activation properties of compounds for GK may be determined using ablack 384-well-plate format under the following reaction conditions: 25mM Hepes pH 7.2, 25 mM NaCl, 10 mM MgCl₂, 0.01% Brij35, 1 mM DTT, 5 μMATP, 5 mM Glucose 2% DMSO. The amount of ATP consumed may be determinedquantitatively by addition of equal volume of luciferase reagent(luciferase+beetle luciferin—KinaseGlo Luminescent Kinase Assay kit fromPromega). The luminescence intensity may be measured by using theAnalyst HT from LJL Biosystems.

The assay reaction may initiated as follows: 4 μl of substrate mixture(12.5 μM ATP and 12.5 mM Glucose) was added to each well of the plate,followed by the addition of 2 μl of activator (2 fold serial dilutionsfor 11 data points for each activator) containing 10% DMSO. 4 μL of 1.25nM GK solution may be added to initiate the reaction. The reactionmixture may then be included at room temperature for 60 min, andquenched and developed by addition of 10 μL of luciferase reagent.Luminescence intensities of the resulting reaction mixtures may bemeasured after a 10 min incubation at room temperature. The luminescenceintensity may be measured by using the Analyst HT from LJL Biosystems.

pK_(act) and % ACT_(max) values may be calculated by non-linear curvefitting of the compound concentration and luminescence intensities to astandard inhibition/activation equation. K_(act) is the concentrationthat displays 50% of the maximal increase in GK activity observed usinga saturating activator concentration. “pK_(act)” is the negative log ofthe K_(act) value; i.e., −log₁₀ [K_(act)]. % ACT_(max) represents thecalculated maximal gain in GK enzyme activity at a saturatingconcentration of the compound. pK_(act) and % ACT_(max) values forselect compounds of the present invention are given Table 1.

TABLE 1 Example pK_(act) % ACT_(max) 2 ≦4.5 >60 3 ≦4.5 50-60 4 ≧5.0 <505 4.6-4.9 <50 6 ≦4.5 50-60 7 ≦4.5 >60 8 ≧5.0 <50 9 4.6-4.9 50-60 11≧5.0 >60 12 4.6-4.9 >60 13 ≧5.0 >60 14 4.6-4.9 >60

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the compounds, compositions,kits, and methods of the present invention without departing from thespirit or scope of the invention. Thus, it is intended that the presentinvention cover the modification and variations of this inventionprovided they come within the scope of the appended claims and theirequivalents.

1. A compound of the formula:

or a ester, tautomer, enantiomer, or pharmaceutically acceptable saltthereof, wherein p is selected from the group consisting of 1, 2, 3, 4,5 and 6; Q is selected from the group consisting of C(═O), C(═S),C(═NR₆), SO and SO₂; U is NR₆; V, W, X, Y and Z are each independentlyCR₄R₅; R₁ is selected from the group consisting ofhetero(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, heteroaryl, andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted; R₂ ishydrogen; R₃ and R₃′ are each independently selected from the groupconsisting of hydrogen, carbonyl, sulfonyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl,(C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted, or R₃ and R₃′ are taken together to form a ring; each R₄and R₅ is independently selected from the group consisting of hydrogen,halo, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,aryl, heteroaryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, with the proviso that R₅ is absent whenthe atom to which it is bound forms part of a double bond; and each R₆is independently selected from the group consisting of hydrogen, oxy,hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy, carbonyl,oxycarbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted, with theproviso that R₆ is absent when the atom to which it is bound forms partof a double bond.
 2. The compound, ester, tautomer, enantiomer, orpharmaceutically acceptable salt according to claim 1 having theformula:


3. The compound, ester, tautomer, enantiomer, or pharmaceuticallyacceptable salt according to claim 1 having the formula:


4. The compound, ester, tautomer, enantiomer, or pharmaceuticallyacceptable salt according to claim 1 having the formula:

wherein n is selected from the group consisting of 0, 1, 2, 3, 4 and 5.5. The compound, ester, tautomer, enantiomer, or pharmaceuticallyacceptable salt according to claim 1 having the formula:


6. The compound, ester, tautomer, enantiomer, or pharmaceuticallyacceptable salt according to claim 1 having the formula:

wherein m is selected from the group consisting of 0, 1, 2, 3 and
 4. 7.The compound according to claim 1 comprising:2-(2H-indazol-2-yl)-4-methyl-N-(thiazol-2-yl)pentanamide;2-(5-fluoro-2H-indazol-2-yl)-4-methyl-N-(thiazol-2-yl)pentanamide;4-methyl-2-(6-nitro-2H-indazol-2-yl)-N-(thiazol-2-yl)pentanamide;4-methyl-2-(6-(methylsulfonyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)pentanamide;2-(5-methoxy-2H-indazol-2-yl)-4-methyl-N-(thiazol-2-yl)pentanamide;2-(5-hydroxy-2H-indazol-2-yl)-4-methyl-N-(thiazol-2-yl)pentanamide;4-methyl-2-(3-methyl-2H-indazol-2-yl)-N-(thiazol-2-yl)pentanamide;2-(5-amino-3-methyl-2H-indazol-2-yl)-4-methyl-N-(thiazol-2-yl)pentanamide;2-(3-amino-2H-methyl-2-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;2-(3-amino-5-fluoro-2H-indazol-2-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;2-(3-amino-5-(methylsulfonyl)-2H-indazol-2-yl)-3-cyclohexyl-N-(thiazol-2-yl)pentanamide;and2-(3-amino-5-(N-methylsulfamoyl)-2H-indazol-2-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide.8. The compound according to claim 1, wherein the compound is in theform of a pharmaceutically acceptable salt.
 9. The compound according toclaim 1, wherein the compound is present a mixture of stereoisomers. 10.The compound according to claim wherein the compound comprises a singlestereoisomer.
 11. The compound, ester, tautomer, enantiomer, orpharmaceutically acceptable salt of claim 1, wherein p is selected fromthe group consisting of 1, 2 and
 3. 12. The compound, ester, tautomer,enantiomer, or pharmaceutically acceptable salt of claim 1, wherein pis
 1. 13. The compound, ester, tautomer, enantiomer, or pharmaceuticallyacceptable salt of claim 1, wherein R₃′ is hydrogen and R₃ is selectedfrom the group consisting of hydrogen, carbonyl, sulfonyl, sulfinyl,(C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,aryl, heteroaryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted.
 14. The compound, ester, tautomer,enantiomer, or pharmaceutically acceptable salt of claim 1, wherein Q isC(═O).
 15. The compound, ester, tautomer, enantiomer, orpharmaceutically acceptable salt of claim 1, wherein Q is C(═S).
 16. Thecompound, ester, tautomer, enantiomer, or pharmaceutically acceptablesalt of claim 1, wherein Q is C(═NR₆).
 17. The compound, ester,tautomer, enantiomer, or pharmaceutically acceptable salt of claim 1,wherein Q is SO.
 18. The compound, ester, tautomer, enantiomer, orpharmaceutically acceptable salt of claim 1, wherein Q is SO₂.
 19. Thecompound, ester, tautomer, enantiomer, or pharmaceutically acceptablesalt of claim 4, wherein n is
 0. 20. The compound, ester, tautomer,enantiomer, or pharmaceutically acceptable salt of claim 4, wherein nis
 1. 21. The compound, ester, tautomer, enantiomer, or pharmaceuticallyacceptable salt of claim 4, wherein n is
 2. 22. The compound, ester,tautomer, enantiomer, or pharmaceutically acceptable salt of claim 1,wherein R₁ is a substituted or unsubstituted hetero(C₃₋₁₂)cycloalkyl.23. The compound, ester, tautomer, enantiomer, or pharmaceuticallyacceptable salt of claim 1, wherein R₁ is a substituted or unsubstitutedheteroaryl.
 24. The compound, ester, tautomer, enantiomer, orpharmaceutically acceptable salt of claim 1, wherein R₁ is selected fromthe group consisting of furanyl, thiophenyl, 2H-pyrrolyl, 1,3-dioxanyl,oxazolyl, thiazolyl, pyrazolyl, 2-pyrazolinyl, isoxazolyl, isothiazolyl,1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl,4H-pyranyl, pyridinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl,thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl,1,3,5-trithianyl, 3-H-indolyl, benzo[b]furanyl, benzo[b]thiophenyl,1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl,isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,1,8-naphthyridinyl, pteridinyl, quinuclidinyl, acridinyl, phenazinyl,phenothiazinyl, and phenoxazinyl, each substituted or unsubstituted. 25.The compound, ester, tautomer, enantiomer, or pharmaceuticallyacceptable salt of claim 1, wherein R₁ is selected from the groupconsisting of oxazolyl, thiazolyl, imidazolyl, 2-imidazolinyl,pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl,1,3,4-thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl,isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,1,8-naphthyridinyl, and pteridinyl, each substituted or unsubstituted.26. The compound, ester, tautomer, enantiomer, or pharmaceuticallyacceptable salt of claim 1, wherein R₁ is a substituted or unsubstitutedthiazolyl.
 27. The compound, ester, tautomer, enantiomer, orpharmaceutically acceptable salt of claim 1, wherein R₁ is a substitutedor unsubstituted pyridinyl.
 28. The, ester, tautomer, enantiomer, orpharmaceutically acceptable salt compound of claim 1, wherein R₃′ isselected from the group consisting of hydrogen and substituted orunsubstituted (C₁₋₃)alkyl.
 29. The compound, ester, tautomer,enantiomer, or pharmaceutically acceptable salt of claim 1, wherein R₃′is hydrogen.
 30. The compound, ester, tautomer, enantiomer, orpharmaceutically acceptable salt of claim 1, wherein R₃ is selected fromthe group consisting of (C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₅)alkyl, and heteroaryl(C₁₋₅)alkyl, each substituted orunsubstituted.
 31. The compound, ester, tautomer, enantiomer, orpharmaceutically acceptable salt of claim 1, wherein R₃ is selected fromthe group consisting of isobutyl, methoxybutyl, methoxypentyl,cyclohexylmethyl, cyclopentylmethyl, cyclopropylmethyl, benzyl,imidazolylmethyl, pyridinylmethyl, pyrrolidinylmethyl, andpiperidinylmethyl, each substituted or unsubstituted.
 32. The compound,ester, tautomer, enantiomer, or pharmaceutically acceptable salt ofclaim 1, wherein R₃ is selected from the group consisting of isobutyland cyclohexylmethyl, each substituted or unsubstituted.
 33. Thecompound, ester, tautomer, enantiomer, or pharmaceutically acceptablesalt of claim 1, wherein at least one R₄ is selected from the groupconsisting of hydrogen, halo, hydroxy, amino, nitro, (C₁₋₃)alkoxy,(C₁₋₃)alkylsulfonyl, aminosulfonyl and (C₁₋₁₀)alkyl, each substituted orunsubstituted.
 34. The compound, ester, tautomer, enantiomer, orpharmaceutically acceptable salt of claim 1, wherein at least one R₄ isselected from the group consisting of amino and (C₁₋₁₀)alkyl, eachsubstituted or unsubstituted.
 35. The compound, ester, tautomer,enantiomer, or pharmaceutically acceptable salt of claim 1, wherein atleast one R₄ is selected from the group consisting of hydrogen, halogenand (C₁₋₃)alkylsulfonyl, each substituted or unsubstituted.
 36. Thecompound, ester, tautomer, enantiomer, or pharmaceutically acceptablesalt of claim 1, wherein at least one R₄ is selected from the groupconsisting of H, F, CH₃, NH₂, SO₂CH₃, SO₂NHCH₃, NO₂, OCH₃ and OH, eachsubstituted or unsubstituted.
 37. The compound, ester, tautomer,enantiomer, or pharmaceutically acceptable salt of claim 1, wherein atleast one R₅ is selected from the group consisting of hydrogen, halogenand (C₁₋₃)alkylsulfonyl, each substituted or unsubstituted.
 38. Thecompound, ester, tautomer, enantiomer, or pharmaceutically acceptablesalt of claim 1, wherein at least one R₅ is hydrogen.
 39. The compound,ester, tautomer, enantiomer, or pharmaceutically acceptable salt ofclaim 1, wherein at least one R₅ is halo.
 40. The compound, ester,tautomer, enantiomer, or pharmaceutically acceptable salt of claim 1,wherein at least one R₆ is selected from the group consisting ofhydrogen, (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl, hetero(C₈₋₁₂)bicycloaryl, each substituted orunsubstituted.
 41. A pharmaceutical composition comprising as an activeingredient a compound according to claim
 1. 42. The pharmaceuticalcomposition according to claim 41, wherein the composition is a solidformulation adapted for oral administration.
 43. The pharmaceuticalcomposition according to claim 41, wherein the composition is a liquidformulation adapted for oral administration.
 44. The pharmaceuticalcomposition according to claim 41, wherein the composition is a tablet.45. The pharmaceutical composition according to claim 41, wherein thecomposition is a liquid formulation adapted for parenteraladministration.
 46. A pharmaceutical composition comprising a compoundaccording to claim 1, wherein the composition is adapted foradministration by a route selected from the group consisting of orally,parenterally, intraperitoneally, intravenously, intraarterially,transdermally, sublingually, intramuscularly, rectally, transbuccally,intranasally, liposomally, via inhalation, vaginally, intraoccularly,via local delivery, subcutaneously, intraadiposally, intraarticularly,and intrathecally.
 47. The compound of claim 1, wherein R₁ is asubstituted or unsubstituted pyrazinyl.
 48. The compound of claim 1,wherein R₁ is a substituted or unsubstituted pyrazolyl.
 49. The compoundof claim 1, wherein R₃ is a substituted or unsubstitutedhetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl.